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 Table of Contents  
REVIEW
Year : 2018  |  Volume : 13  |  Issue : 10  |  Page : 1719-1730

Distinguishing normal brain aging from the development of Alzheimer's disease: inflammation, insulin signaling and cognition


1 Greater Los Angeles Veterans Affairs Healthcare System, West Los Angeles Medical Center and Department of Neurology, University of California, Los Angeles, CA, USA; Centre for Molecular Biosciences, University of Ulster, Coleraine, Northern Ireland, UK
2 Northern Ireland Centre for Stratified Medicine, Clinical, Translational and Research Innovation Centre (C-TRIC), University of Ulster, Derry/Londonderry, Northern Ireland, UK

Date of Acceptance16-Jul-2018
Date of Web Publication23-Aug-2018

Correspondence Address:
Paul Denver
Greater Los Angeles Veterans Affairs Healthcare System, West Los Angeles Medical Center and Department of Neurology, University of California, Los Angeles, CA, USA; Centre for Molecular Biosciences, University of Ulster, Coleraine, Northern Ireland, UK

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Source of Support: This work was supported by the Department of Education and Learning, Northern Ireland, UK, Conflict of Interest: Some of the data from Denver et al. (2018) has been submitted, in abstract form, to the 2017 Southern California Alzheimer抯 Disease Centers Research Symposium at the University of California, Beckman Center of the National Academies of Sciences & Engineering, Irvine, CA, USA


DOI: 10.4103/1673-5374.238608

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  Abstract 


As populations age, prevalence of Alzheimer's disease (AD) is rising. Over 100 years of research has provided valuable insights into the pathophysiology of the disease, for which age is the principal risk factor. However, in recent years, a multitude of clinical trial failures has led to pharmaceutical corporations becoming more and more unwilling to support drug development in AD. It is possible that dependence on the amyloid cascade hypothesis as a guide for preclinical research and drug discovery is part of the problem. Accumulating evidence suggests that amyloid plaques and tau tangles are evident in non-demented individuals and that reducing or clearing these lesions does not always result in clinical improvement. Normal aging is associated with pathologies and cognitive decline that are similar to those observed in AD, making differentiation of AD-related cognitive decline and neuropathology challenging. In this mini-review, we discuss the difficulties with discerning normal, age-related cognitive decline with that related to AD. We also discuss some neuropathological features of AD and aging, including amyloid and tau pathology, synapse loss, inflammation and insulin signaling in the brain, with a view to highlighting cognitive or neuropathological markers that distinguish AD from normal aging. It is hoped that this review will help to bolster future preclinical research and support the development of clinical tools and therapeutics for AD.

Keywords: Alzheimer′s disease; aging; inflammation; cognitive function; spatial learning; insulin signaling; synapses; cytokines


How to cite this article:
Denver P, McClean PL. Distinguishing normal brain aging from the development of Alzheimer's disease: inflammation, insulin signaling and cognition. Neural Regen Res 2018;13:1719-30

How to cite this URL:
Denver P, McClean PL. Distinguishing normal brain aging from the development of Alzheimer's disease: inflammation, insulin signaling and cognition. Neural Regen Res [serial online] 2018 [cited 2020 Feb 27];13:1719-30. Available from: http://www.nrronline.org/text.asp?2018/13/10/1719/238608

Paul Denver, Paula L. McClean. These authors contributed equally to this work.





  Introduction Top


Normal aging is associated with deterioration of cognitive function and accumulation of neuropathological lesions that can also occur in Alzheimer's disease (AD). Distinguishing AD from normal aging, particularly in the earliest stages, allows for more thorough clinical characterization of abnormal cognitive decline and can also provide insights into AD pathophysiology that may ultimately support drug discovery, an element of the AD field that is currently lacking. Since its inception, the amyloid cascade hypothesis has bolstered AD research and helped progress the field immensely, however a fixation on this model may be hindering scientific advances and drug development. We will briefly describe some of the difficulties with defining abnormal cognitive deterioration, outline some issues associated with traditional AD neuropathology as correlates of cognitive dysfunction and discuss aspects of synapse loss, inflammation and insulin signaling in the brain as potentially distinct in AD versus normal aging. Consistent clinical trial failures for drugs aimed at treating AD based on the predictions of the amyloid cascade hypothesis have led several pharmaceutical companies to abandon their support for trials aimed at developing AD therapeutics, leading to a significant disparity between AD drug development and disease prevalence, which is predicted to continue rising as global populations age. This mini-review aims to summarize recent clinical and pre-clinical findings related to inflammation, insulin signaling and cognition in AD and aging. It is hoped that this will highlight gaps in knowledge and encourage progression of research aiming to distinguish the development of AD from normal aging.


  Differentiating Abnormal from Normal Cognitive Decline Top


As the quality and availability of healthcare continues to improve around the world, average life expectancy is being extended (Timonin et al., 2016), such that prevalence of diseases associated with aging is growing (Murray et al., 2013). AD is a progressive neurodegenerative disease, for which advancing age is a major risk factor (Querfurth and LaFerla, 2010). It is the most common form of dementia (Barnes and Yaffe, 2011) and estimates suggest that as of 2015, there were 47 million people worldwide living with AD, a number that is projected to rise to 131 million by 2050 (Rizzi et al., 2014; Baumgart et al., 2015). Several clinical and neuropathological features of dementia and AD may also be evident with the normal progression of aging, making distinction of abnormal development of dementia from normal brain aging challenging. In AD, there is a long prodromal period during which the disease progresses sub-clinically for decades (Chertkow et al., 2013). When clinical symptoms eventually become apparent, pathology in the brain is well established and intervention is seldom effective and can only slow progression of the disease (Casey et al., 2010). The ability to identify AD as early as possible would provide patients and clinicians with opportunities to intervene prior to the establishment of irreversible neuropathology. The characterization of mild cognitive impairment (MCI) as a clinical entity, distinct from AD, but also considered abnormal (Petersen et al., 1999; Grundman et al., 2004) allowed for the definition of a pattern of decline that was similar to, but divergent from normal aging. After 60 years of age, impairments of some cognitive abilities such as processing speed, working memory and executive functions become apparent, while others, such as short-term memory, autobiographical knowledge and emotion processing remain relatively intact (Hedden and Gabrieli, 2004; Folstein and Folstein, 2010). Patients with MCI are said to have alterations in cognition with noticeable decline, while retaining functional independence (Winblad et al., 2004). A diagnosis of dementia due to AD is made when a patient's cognitive decline is so severe that it diminishes independent living (Swerdlow, 2011). Generally, healthy aging is associated with moderate decline in some cognitive abilities, whilst AD is characterized by severe deterioration of the same cognitive domains, with additional progressive decline of further cognitive functions, such that the patient's personal, professional and social life is adversely affected to a severe degree (McKhann et al., 2011; Swerdlow, 2011). The concept of “subjective cognitive decline” has been investigated in recent years as an even earlier indication of AD (Rabin et al., 2017) and evidence suggests that subjective cognitive decline may predict faster conversion to MCI and AD (Fernandez-Blazquez et al., 2016).


  Plaques and Tangles Are Poor Correlates of Cognitive Decline in AD Top


Traditional neuropathological lesions in AD brain include senile plaques, consisting of aggregated amyloid-β (Aβ) and neurofibrillary tangles (NFT) of tau protein, which accumulate extracellularly and intraneuronally, respectively (De-Paula et al., 2012; Reitz and Mayeux, 2014). Enhanced neuroinflammation is also consistently observed in AD (McGeer and McGeer, 2013; Meraz-Rios et al., 2013) and evidence suggests that early hyperactivity of pro-inflammatory pathways in the brain precedes the development of plaques and tangles in AD (Tarkowski et al., 2003; Ferretti and Cuello, 2011; Wright et al., 2013). Muddying the waters, however, is the fact that aging itself is associated with similar aberrations in the brain, that may or may not lead to cognitive deterioration. Accumulating evidence suggests that Aβ plaques and neurofibrillary tau tangles are not uncommon in the brains of non-demented, cognitively healthy older people (Price and Morris, 1999; Savva et al., 2009; Malek-Ahmadi et al., 2016). Evidence has also shown that Aβ deposition correlates poorly with cognitive impairment in elderly cohorts (Terry et al., 1991; Aizenstein et al., 2008; Malek-Ahmadi et al., 2016), suggesting that Aβ per se does not directly influence cognitive function. Indeed, we recently found that although Aβ deposition was significant in brains of aged APP/PS1 mice, a model of AD, and virtually absent from age-matched controls, both groups of aged mice performed equally poorly on several cognitive tasks (Denver et al., 2018). Although the amyloid cascade hypothesis remains the dominant paradigm that attempts to explain the pathogenesis of AD (Hardy and Allsop, 1991; Hardy and Higgins, 1992; Hardy and Selkoe, 2002), consistent anti-amyloid drug trial failures have bolstered criticism of the model that considers misprocessing of amyloid the central pathological event in AD (Drachman, 2014; Herrup, 2015). Musiek and Holtzman (2015) reviewed recent evidence for and against the amyloid cascade hypothesis and concluded that Aβ was critical, but not sufficient for the development of AD. They proposed an updated model that incorporates the idea that a balance is maintained throughout life between production and clearance of Aβ in the brain. Factors that increase AD risk occurring in midlife then contribute to disruption of this homeostatic balance, which leads to overproduction and reduced clearance of Aβ and subsequent pathological cascades and clinical signs of the disease (Musiek and Holtzman, 2015). In any case, improvements in cognitive performance can occur independently of effects on Aβ (Kotilinek et al., 2002; Hock et al., 2003; Chen et al., 2007) and reductions of Aβ pathology don't always correlate with improved cognition, nor does reducing amyloid burden always slow progression of neurodegeneration (Holmes et al., 2008; Kokjohn and Roher, 2009). It seems more and more likely that amyloid, particularly in the insoluble plaque form, is not the necessary and sufficient factor initially posited by Hardy and Allsop (1991), but rather a downstream event or byproduct of other known or unknown mechanisms in AD brain. Prefibrillar, soluble Aβ aggregates in the form of oligomers have recently been appreciated as specifically synaptotoxic and neurotoxic (Ferreira et al., 2015). In fact, it has been known for 20 years that the small, soluble aggregations of Aβ, described at the time as Aβ-derived diffusible ligands (ADDLs), are neurotoxic independent of larger Aβ fibrils and plaques and may mediate the progressive cognitive deterioration in AD (Lambert et al., 1998; Shi et al., 2016). Aβ oligomers (AβOs) have been included in more recent revisions of the amyloid cascade hypothesis (Klein et al., 2001; Hardy and Selkoe, 2002), suggesting that soluble AβOs, rather than larger fibrils or plaques, elicit synaptic toxicity and memory dysfunction (Ferreira and Klein, 2011; Gulisano et al., 2018). NFT of hyperphosphorylated tau protein in AD brain have been considered a more reliable correlate of cognitive decline in AD patients (Arriagada et al., 1992; Nelson et al., 2012). Tau is a microtubule-associated protein that supports and stabilizes the neuronal cytoskeleton (Brandt and Lee, 1993; Panda et al., 1995; Johnson and Stoothoff, 2004). In AD, aberrant hyperphosphorylation of tau reduces its ability to bind and stabilize microtubules (Lu and Wood, 1993) and promotes self-aggregation into paired helical filaments and subsequently, NFT (Garcia de Ancos et al., 1993; Johnson and Stoothoff, 2004). Hyperphosphorylated tau is also directly neurotoxic (Fath et al., 2002; Chun and Johnson, 2007) and neuronal apoptosis induced by tau aggregates is thought to at least partially underlie some of the degeneration and cognitive decline associated with AD (Arriagada et al., 1992; Johnson and Stoothoff, 2004). However, since tangles of hyperphosphorylated tau have frequently been observed in brains of non-demented individuals (Price et al., 1991; Price and Morris, 1999), it seems likely that while tau hyperphosphorylation may be involved with AD pathophysiology, tangle pathology may not be as reliably correlated with cognitive decline as previously thought. Several studies have shown that pre-tangle oligomeric tau species are elevated in neurons from AD brain (Tiernan et al., 2018), an effect that correlates negatively with cognitive function (Vana et al., 2011), suggesting that tau oligomers are toxic in AD brain and their levels may correlate more robustly with cognitive decline.

Classical pathological lesions in AD brain, amyloid and tau deposits are used as measures of disease progression and also as an indicator of therapeutic efficacy. However, given the paucity of consistent correlations between these markers and cognitive decline, future studies may wish to consider alternative pathological measures, including oligomeric amyloid and tau. Additionally, in pre-clinical studies, investigators should consider the possibility that non-transgenic control animals may also develop similar age-dependent pathologies in the brain. Future experimental designs should include additional groups of younger animals, such that age-dependent changes in cognitive function or brain pathologies in control animals can be identified.


  Is Spatial Learning Particularly Susceptible to Alzheimer's Pathology? Top


With advancing age, impairments of some cognitive abilities become increasingly apparent, while others remain relatively intact in otherwise healthy individuals (Folstein and Folstein, 2010). Spatial learning impairments, using the Morris water maze, have been well-documented in the APP/PS1 mouse model of AD, at 12 (Harrison et al., 2009; Xiao et al., 2016), 13–14 (Jia et al., 2013; Fol et al., 2016) and 22–24 (Harrison et al., 2009; Xiao et al., 2016) months of age, while learning has been found to be unimpaired in APP/PS1 mice aged 7 months (O’Reilly and Lynch, 2012). Recently, we demonstrated impaired spatial learning in 15–18 month-old APP/PS1 mice, compared to ‘healthy’, age-matched controls, while spatial memory retention and recognition memory were similarly impaired in both groups (Denver et al., 2018). This suggests that spatial learning is a cognitive process that is especially defective in AD. Reversal learning was notably impaired in APP/PS1 mice (Denver et al., 2018), similar to findings in younger APP/PS1 mice (O’Reilly and Lynch, 2012; Cheng et al., 2014), suggesting that cognitive flexibility is vulnerable to the effects of AD pathology. Given the memory impairments in aged wild-types, as well as transgenic mice, it seems reasonable to suggest that spatial and recognition memory are deleteriously affected with aging, while spatial learning is distinctly vulnerable to AD pathology (Denver et al., 2018). Interestingly, certain spatial cognitive domains are also known to be impaired in aged C57Bl/6 mice (Barreto et al., 2010; Shoji et al., 2016).

Other amyloidogenic mouse models of AD show similar alterations in cognitive function. Age-dependent deficits of spatial learning have been detected in tg-ArcSwe mice, which express both Arctic and Swedish mutations of APP (Lord et al., 2009). Some (Wolf et al., 2016; Portbury et al., 2017), but not all (Bizon et al., 2007) have observed learning and memory impairments in aged adult Tg2576 mice, while early cognitive deficits have been detected in the 3xTg AD model (Stover et al., 2015). Most AD mouse models develop spatial learning and memory impairments, however AD is a complicated basket of interconnected pathologies, making identification of the precise cause of AD-related cognitive dysfunction challenging. Recent appreciation for impaired spatial navigation as a cognitive domain that can distinguish incipient AD or MCI from aging in humans (Lithfous et al., 2013; Coughlan et al., 2018) has spurred empirical investigation, results of which suggest that this may indeed be the case (Allison et al., 2016). These findings may inform future clinical and pre-clinical AD research and may support clinicians in identifying early patterns of cognitive decline that are divergent from normal aging.


  Synaptic Loss in AD and Aging Top


Synapse loss consistently correlates with cognitive decline in AD (Terry et al., 1991; Shankar and Walsh, 2009; Robinson et al., 2014). Several studies have shown that synapse density is decreased in the brains of 5–8 month-old APP/PS1 mice (McClean et al., 2011; Zhang et al., 2014; Li et al., 2015; Liu et al., 2016), while others report reduced synapse density in brains of 18–24-month-old APP/PS1 mice, compared to age-matched wild-types (Ostapchenko et al., 2015; Zhang et al., 2016). However, one report showed that synaptophysin levels in the hippocampus of 7- and 17-month-old APP/PS1 mice were similar to age-matched wild-types (Minkeviciene et al., 2008). Our results suggest that hippocampal and cortical synapse density is comparable between 15–18 month-old wild-types and APP/PS1 mice (Denver et al., 2018), possibly reflecting age-related synapse loss. A number of the aforementioned studies identified reduced synaptophysin levels using western blot assay of hippocampal and cortical homogenates (Li et al., 2015; Liu et al., 2016; Zhang et al., 2016) or by quantitative analysis of synaptophysin immunofluorescence throughout the whole hippocampus (Li et al., 2015; Ostapchenko et al., 2015). Unlike methods utilized by Denver et al. (2018), neither of these methods considered the discrete cellular layers of the hippocampus and therefore may have overlooked subtle variation in synapse density between subregions in APP/PS1 and wild-type mice. It has been shown in Tg2576 mice that synaptophysin levels were no different from controls at 3, 9, 14 and 19 months of age (King and Arendash, 2002). Additionally, evidence suggests that synaptophysin levels are unaffected in the hippocampus of human patients with AD (Tannenberg et al., 2006; Counts et al., 2012). In aged APP/PS1 mice, Malthankar-Phatak et al. (2012) failed to detect reduced synaptophysin staining in the hippocampal molecular layer or neocortical areas, even at 24–27 months of age, results that more closely align with our findings (Denver et al., 2018). We did, however, detect reduced synaptophysin staining in the polymorphic hilar layer of the dentate gyrus in aged APP/PS1 mice, compared to controls (Denver et al., 2018). Others have shown AD-related synapse loss in the inner (Scheff and Price, 1998) and outer (Scheff et al., 1996; Alonso-Nanclares et al., 2013) molecular layers of the dentate gyrus. Synapse loss in the outer molecular layer and layers II and III of the entorhinal cortex has also been demonstrated in Tg2576 mice by electron microscopy, while synaptophysin levels remained unchanged (Dong et al., 2007). There are several potential explanations for the variation in the findings from the aforementioned studies. First of all, markers typically utilized when measuring synapse density in the brain represent functional proteins in either the pre- or post-synaptic terminal. In AD and aging, reductions of synaptic marker levels may represent loss, dysfunction or mislocalisation of distinct synaptic proteins, rather than a general loss of synapses. Furthermore, there are a huge number of synaptic proteins that comprise synapses, the majority of which can be used as biomarkers of synapse density. This means that depending on a single or even several markers to assess synapse density may be problematic if there are selective alterations of distinct proteins, rather than simply synapse loss, as has been reported (Tannenberg et al., 2006). Secondly, AD and aging may be associated with a loss of pre- or post-synaptic terminals at different stages as the disease or age progresses. Counts et al. (2012) found that pre-synaptic synaptophysin and synaptotagmin were unaltered in the hippocampus of AD and MCI patients, whereas post-synaptic drebrin was reduced. Had the authors failed to include drebrin in their analysis, they may have erroneously concluded that MCI and early AD is not associated with synapse loss in the hippocampus (Counts et al., 2012). The third potential reason for the inconsistent findings is the regional heterogeneity of synapse loss in the brain with aging and in AD. There is a general consensus that synapse loss is primarily apparent in the hippocampus, as well as frontal and temporal cortices of AD patients (Clare et al., 2010), however these anatomical regions consist of a number of distinct subregions that are connected with other areas within complex neuronal circuits. Inconsistencies may arise in the literature simply as a result of investigators not looking in the correct place within the brain, or not looking closely enough. Where possible, studies that measure synapse density using antibody-mediated immunostaining or biochemical assays may also wish to examine synapse ultrastructure using electron microscopic techniques, with which functional synaptic contacts can be directly visualized (Dong et al., 2007; Neuman et al., 2015).

The polymorphic layer of the dentate gyrus contains several different types of neuron, the most abundant of which is the mossy cell neuron (Amaral et al., 2007). Mossy cells in the hilus provide inhibitory and excitatory input to neurons in the adjacent granule cell layer (Buckmaster et al., 1996). They also form synaptic connections with another polymorphic layer cell, the GABAergic inhibitory interneuron, which in turn can inhibit granule cell neurons (Scharfman, 1995). This complex network of inhibitory and excitatory activity is thought to underlie certain forms of associative memory and pattern separation (Myers and Scharfman, 2011; Scharfman and Myers, 2012). The decrease in synaptophysin levels in the polymorphic layer of aged APP/PS1 mice (Denver et al., 2018) could indicate a reduction in mossy cell synaptic contact with inhibitory interneurons, which would result in disinhibition of granule cell neurons and disruption of the fine balance of inhibitory and excitatory neuronal activity required for effective cognitive functioning. It has been shown that enhancing GABAergic innervation in the dentate gyrus improves reversal learning in mice (Morellini et al., 2010). The consequences of synaptic dysfunction within this discrete subregion of the hippocampus remain to be fully determined. Based on our results, one may speculate that hilar synapse loss is responsible for the observed impairment in spatial learning, particularly reversal learning, since the neural network associated with the hilus of the dentate gyrus is involved with pattern separation and reversal learning (Scharfman and Myers, 2012).

Aging in humans is also associated with reduced levels of synaptic proteins related to structural plasticity of axons and dendrites, while in human AD brain there is an additional reduction of postsynaptic drebrin (Hatanpaa et al., 1999). Age-related correlations between hippocampal synapse loss and cognitive decline are known to exist (Nicholson et al., 2004; Nyffeler et al., 2007; Long et al., 2009), although some report a lack of such a relationship (Geinisman et al., 2004). Age-related deficits in hippocampal long-term potentiation (LTP) have also been identified (Deupree et al., 1993; Barnes et al., 1997; Bouet et al., 2011), suggesting that a decline in synaptic function with age, rather than synapse density as such, is more closely linked with cognitive decline. Support for this proposal has been presented in several reports that demonstrated a reduction, as a consequence of aging, of pre- and post-synaptic components required for efficient functioning of synapses in the hippocampus (Canas et al., 2009; Long et al., 2009; VanGuilder et al., 2010). Conversely, increased expression of synaptic proteins is associated with superior learning in aged animals (Colombo and Gallagher, 2002; Menard and Quirion, 2012). These studies demonstrate the importance of intact, functional synapses, particularly in the hippocampus, in learning and memory. Deterioration of synaptic integrity and synapse loss in AD brain and with aging may explain at least some of the cognitive deficits apparent in animal models and humans. Comparing synapse loss in AD brain with that associated with aging will require delineation of regional vulnerability of synapses to aging or AD pathology and correlations with specific cognitive deficits. It should also be remembered that synaptic biomarkers represent functional proteins within the synapse and modulation of these proteins may reflect dysfunction of the protein itself, rather than loss of the entire synapse. Pre- and post-synaptic terminals and the proteins of which they are comprised likely respond differently to AD and aging pathologies. Inclusion of at least one pre-synaptic and one post-synaptic marker would provide more reliable insights into synaptic dysfunction associated with AD and aging. Where possible examining synaptic ultrastructure with electron microscopy would also greatly enhance the reliability of future research.


  The Complexity of Neuroinflammation in AD and Aging Top


Microglia and astrocytes are able to initiate an inflammatory response to injury in the central nervous system (CNS) (Kreutzberg, 1996; Schilling et al., 2003; Rezai-Zadeh et al., 2009). Aβ rapidly activates microglia, such that their morphological and phenotypic characteristics are altered to promote phagocytosis and induce a focal inflammatory response, leading to recruitment of other immune cells (Koenigsknecht and Landreth, 2004; Meraz-Rios et al., 2013). Activated microglia phagocytose Aβ and reduce amyloid burden (Bard et al., 2000; Lee and Landreth, 2010; El-Shimy et al., 2015; Fu et al., 2016). However, sustained microglial activation and unresolved inflammation in the brain is harmful to neurons and synapses and promotes a state of chronic dysregulation of glial cells and subsequent deterioration of brain structure and function (Frank-Cannon et al., 2009; Steardo et al., 2015; Leszek et al., 2016). Aβ42 can induce microglial phagocytosis of viable neurons (Neniskyte et al., 2011, 2016; Fricker et al., 2012) and phagocytic microglia are thought to contribute to synapse loss early in AD (Hong et al., 2016). Microglia secrete an array of pro-inflammatory cytokines and chemokines, such as interleukin (IL)-6, IL-1β, tumor necrosis factor α (TNF-α), macrophage inflammatory protein-1α (MIP-1α) and monocyte chemotactic protein 1 (MCP-1), when exposed to Aβ (Rogers and Lue, 2001; Patel et al., 2005; Tuppo and Arias, 2005). This leads to recruitment and activation of astrocytes and peripheral immune cells (Rezai-Zadeh et al., 2009). Astrocytes are also recruited to Aβ plaques (Wyss-Coray et al., 2003) and are also capable of degrading Aβ (Nagele et al., 2003; Wyss-Coray et al., 2003; Koistinaho et al., 2004), albeit less efficiently than microglia (Mandrekar et al., 2009). Although it has been posited that astrocyte migration is induced by Aβ-mediated injury to adjacent neurons, as opposed to Aβ per se (Galea et al., 2015).

Inflammation in the brain increases with age (Lynch, 2010; Gabuzda and Yankner, 2013) and several studies report elevated levels of inflammatory cytokines in brains of aged rodents (Ye and Johnson, 1999; Maher et al., 2004; Godbout et al., 2005). Since aging is also associated with systemic augmentation of inflammation (Franceschi et al., 2007) it is thought that circulating inflammatory mediators prime microglia in the aging brain (Perry, 2004; Dilger and Johnson, 2008; Norden and Godbout, 2013; Matt and Johnson, 2016). Primed microglia are more pro-inflammatory at baseline, are more sensitive to secondary immune challenges and generate an exaggerated inflammatory response (Lull and Block, 2010; Norden et al., 2015; Wendeln et al., 2018). In the context of AD, primed microglia respond more readily to Aβ, producing enhanced levels of cytokines and exerting direct toxic effects on neurons and at synapses (Hong et al., 2016; Spangenberg et al., 2016). Therefore, dysregulation of the systemic and central immune system that accompanies aging can serve as a chronic priming stimulus for microglia (Godbout et al., 2005; Norden and Godbout, 2013; Wendeln et al., 2018); a mechanism that could mediate the increased risk of AD with age (Querfurth and LaFerla, 2010).

Polymorphisms in genes encoding several cytokines are strongly associated with increased risk of AD, including IL-1β, IL-6, interferon γ (IFNγ), IL-4 and IL-10 (Licastro et al., 2007; Zhang et al., 2011; Hua et al., 2013; Zheng et al., 2016; Dong et al., 2017), suggesting an association between cytokines and either protection against or propagation of AD pathogenesis. In our recent study we found comparable levels of inflammatory cytokines in the brain of aged wild-type and APP/PS1 mice, with the exception of IFNγ and IL-4, which were both elevated in APP/PS1 mice (Denver et al., 2018). The similarities in inflammatory profile in the brain of aged mice may be related to the general enhancement of neuroinflammation evident with aging. Elevated IFNγ has been shown previously in the brain of younger APP/PS1 mice, the cellular source of which was infiltrating Aβ-specific T cells (Browne et al., 2013). Interestingly, adoptive transfer of Th1-producing T cells to APP/PS1 mice resulted in microglial activation, increased Aβ deposition and cognitive dysfunction (Browne et al., 2013). Given the negative correlation, demonstrated in our study, between brain IFNγ levels and recognition memory (Denver et al., 2018), it may be that enhanced brain levels of IFNγ has a direct negative impact on cognitive function in AD. In any case, it appears that IFNγ and IL-4 were specifically increased in the brains of APP/PS1 mice, presumably as an effect of AD pathology. Increased brain levels of IFNγ has also been shown in APPswe mice aged 3 and 19 months (Abbas et al., 2002), however brain IL-4 was down-regulated in this study, contrary to our findings. Th2 cytokine IL-4 plays a role in suppressing Th1 immune responses (Luzina et al., 2012), as such, our findings may represent protective upregulation of IL-4 in the brains of APP/PS1 mice as a response to elevated levels of IFNγ (Denver et al., 2018), while results of Abbas et al. (2002) might reflect a failure of this protective response in APPswe mice. Important sources of IFNγ and IL-4 include T lymphocytes (Castro et al., 2018). It is possible that circulating or infiltrating T cells or macrophages in the CNS are responsible and may be involved in the pathophysiology of AD, a proposition that is increasingly under investigation (Browne et al., 2013). Microglia and astrocytes also produce IFNγ (Lau and Yu, 2001; Kawanokuchi et al., 2006; Wang and Suzuki, 2007; Sa et al., 2015), while evidence suggests that although astrocytes may not produce IL-4, they do express the IL-4 receptor, through which they respond to IL-4 by suppressing inflammatory activation and augmenting growth factor production (Brodie et al., 1998; Liu et al., 2000). Sources of IL-4 in the brain include microglia and neurons (Zhao et al., 2015; Lee et al., 2016). Neuronal IL-4 has been shown to induce a restorative M2-like phenotype in microglia (Fernandes et al., 2014; Zhao et al., 2015), while Latta et al. (2015) also showed that IL-4 was involved in the induction of an M2a phenotype in microglial cells and in the brains of APP/PS1 mice. Together this suggests that IL-4, possibly derived from microglia, neurons or infiltrating T cells, exerts neuroprotective effects in models of brain injury, including AD. Intriguingly, IL-4 may also exert direct, beneficial effects on cognitive function (Gadani et al., 2012), suggesting that the clinical manifestation of AD or age-related cognitive decline may be associated with direct effects of cytokines, including IL-4 (McAfoose and Baune, 2009; Derecki et al., 2010).

Pro-inflammatory IL-1β has been consistently associated with AD (Mrak and Griffin, 2001; Shaftel et al., 2008). Several reports indicate that IL-1β is up-regulated in plasma from MCI and AD patients (De Luigi et al., 2002; Forlenza et al., 2009; Brosseron et al., 2014) and previous studies have detected increased levels of IL-1β in brains of APP/PS1 mice (Gallagher et al., 2013; Yan et al., 2013; Guo et al., 2015; Xuan et al., 2015). An inactive precursor of IL-1β (pro-IL-1β) is present in glial cells in the brain (Shaftel et al., 2008) and activation of IL-1β is dependent on caspase-1 cleavage of pro-IL-1β (Halle et al., 2008). The inflammasome NLRP3 detects danger signals through toll-like receptor 4 (TLR4) signaling in astrocytes and microglia (Alfonso-Loeches et al., 2014, 2016). It has been demonstrated that Aβ stimulates IL-1β production and secretion via NLRP3-dependent cleavage of pro-IL-1β by caspase-1 (Halle et al., 2008; Salminen et al., 2008; Heneka et al., 2013; Parajuli et al., 2013), providing a reasonable mechanistic explanation for the elevated levels of IL-1β in AD brain. However, elevated levels of IL-1β have also been shown in brains of senescence-accelerated SAMP8 mice (Tha et al., 2000) and in aged rat brain (Gee et al., 2006; Campuzano et al., 2009). We also detected elevated IL-1β in brains of both aged C57Bl/6 and APP/PS1 mice, compared to young wild-type mice (Denver et al., 2018). In addition, IL-1β has been shown to suppress hippocampal LTP (Vereker et al., 2000; Griffin et al., 2006; Hoshino et al., 2017; Prieto et al., 2018), suggesting that IL-1β might partially mediate cognitive dysfunction in aging and AD.


  Perturbed Insulin Signaling in AD Brain Top


A reciprocal relationship exists between AD risk and type 2 diabetes mellitus (T2DM), another disease associated with aging (Janson et al., 2004; Mittal and Katare, 2016). One of several similarities with AD, inflammation is also an important feature of T2DM pathophysiology (Lontchi-Yimagou et al., 2013). Resistance of systemic tissues, such as adipose tissue and pancreas, to the hormone insulin is another significant feature of T2DM (Taylor, 2012). Activation of the insulin receptor (IR) is followed by recruitment of insulin receptor substrate (IRS) proteins intracellularly, usually IRS-1 or IRS-2 (White, 2003; Boura-Halfon and Zick, 2009). The insulin-mediated signaling cascade then continues via phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt), among several others, eliciting downstream effects through phosphorylation and activation of other kinases and effector molecules (Siddle, 2011). Normal inhibition of IRS-1 is a means by which insulin signaling is regulated and is mediated by mitogen-activated protein kinases (MAPK), such as extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinases (JNK) and inhibitor of κB kinase (IKK) (Gao et al., 2002, 2004; Boura-Halfon and Zick, 2009). This down-regulation of insulin signaling can occur through phosphorylation of serine residues on IRS-1, including those at positions 307 (Hirosumi et al., 2002), 312 (Gao et al., 2002) and 616 (Talbot et al., 2012). These intracellular kinases can be modulated by extracellular factors such as oxidative and nitrosative stress, inflammatory mediators and Aβ oligomers (Dineley et al., 2001; Andreozzi et al., 2007; Giordano et al., 2008; Bomfim et al., 2012), which, through activation of respective membrane-bound receptors, are able to influence inhibitory serine phosphorylation of IRS-1. Aging itself is associated with development of glucose intolerance and insulin resistance (Fink et al., 1983; Rowe et al., 1983; Paolisso et al., 1999; Barbieri et al., 2001). Park et al. (2013) identified numerous insulin signaling genes that were down-regulated in aged rodents and other reports suggest that insulin insensitivity and glucose intolerance also exists in aged animals (Catalano et al., 2005; Yamamoto and Otsuki, 2006; Romanatto et al., 2014), including C57Bl/6 mice (Houtkooper et al., 2011; Lipina et al., 2016). Insulin resistance has been demonstrated in postmortem brain tissue from AD and MCI patients, in the absence of diabetes and irrespective of apolipoprotein E (ApoE)-ε4 status (Talbot et al., 2012). Furthermore, IRS-1 pSer616 and IRS-1 pSer636/639 were identified as putative biomarkers of brain insulin resistance in AD and were found to correlate positively with Aβ oligomer levels and negatively with cognitive function (Talbot et al., 2012). Another study showed similar results in human AD brain tissue and also found that stimulation of primate hippocampus and hippocampal neuronal cultures with Aβ oligomers, increased levels of IRS-1 pSer636 and activated JNK; a stress kinase that phosphorylates IRS-1 at serine residues (Bomfim et al., 2012). Other studies have also demonstrated impaired neuronal insulin signaling in AD brain and in response to Aβ oligomer challenge at the level of the IR and insulin-like growth factor-1 (IGF-1) receptor, IRS-1, IRS-2, PI3K and Akt (Zhao et al., 2008; Moloney et al., 2010; Liu et al., 2011). In the brain, insulin signaling encourages proliferation, differentiation, neurite growth and is anti-apoptotic and neuroprotective (Blazquez et al., 2014). Furthermore, insulin modulates the structure and function of synapses, neurons and neural circuits and has a well-established role in enhancing learning and memory (Blazquez et al., 2014). This suggests that insulin resistance in the brain can exist as a distinct phenomenon, independent of peripheral insulin resistance and glucose intolerance (Bomfim et al., 2012; Talbot et al., 2012). This also implies that diminished responsiveness to insulin in the brain has different consequences than in peripheral tissues. Our data shows that peripheral insulin and glucose tolerance were comparable between aged wild-type and APP/PS1 mice, while IRS-1 pSer616 levels were increased in the brain of APP/PS1 mice (Denver et al., 2018). This provides some support for the suggestion that insulin resistance in brain may indeed exist as a distinct phenomenon, separate from insulin signaling in the periphery and one that can distinguish AD from normal aging.


  Perspectives and Future Directions Top


The differentiation of normal brain aging from development of AD is necessary to allow for the categorization of risk of progression from MCI to AD. This will identify potential treatment windows and inform decisions regarding lifestyle interventions aimed at reducing the risk of developing AD. The role of inflammation in AD is complex, with dichotomous functions in the preservation or deterioration of brain structure and function. Clinical success for pharmacological interventions in AD that either boost or suppress inflammatory responses in the brain have been relatively sparse, ie. amyloid immunization and NSAID trials. Glial cells function as active immune cells and protect the CNS from pathogenic insults, including Aβ, however, persistent immunological activation of these cells drives the development of a neurotoxic pro-inflammatory environment and reduces their ability to function as homeostatic regulators in brain. In addition to the direct toxic effects elicited by pro-inflammatory glial cells, future research should also consider the potential gaps in potassium buffering, lactate shuttling, glutamate recycling and synaptic stripping that may be evident within the inflammatory milieu of AD brain. Such studies would illuminate novel therapeutic potential aimed at maintaining or restoring homeostatic functions of multifunctional glial cells, rather than broad inhibition or stimulation. In addition to CNS-resident glial cells, future studies should address the contribution of peripheral immune cells, such as lymphocytes and neutrophils, to the neuroinflammatory environment in AD brain. This systemic immune response may be beneficial or harmful to the integrity of the CNS in AD and greater understanding may help to identify novel therapeutic targets for a disease in which effective treatment is notoriously difficult. Dysregulated insulin signaling in AD brain has been recently appreciated and our work supports the proposition that brain insulin resistance distinguishes AD from healthy aging. Further work is needed to clarify the precise molecular and cellular players in this story. Future investigations should determine changes in kinase and phosphatase activity that develop in AD brain, particularly those that interact with IRS-1. Moreover, what are the functional consequences of downregulated insulin signaling in the brain? Likely effects include increased neuronal apoptosis, tau hyperphosphorylation and cognitive dysfunction, however, the complexity of AD makes it difficult to delineate direct cause and effect pathways. Insulin-sensitizing drugs may prove efficacious in treating AD and early clinical trial data suggest that incretin hormone derivatives do indeed have several positive effects in brain. Finally, we identified spatial learning as a particularly defective cognitive domain specifically in AD mice. Although it is well-known that spatial learning and memory is impaired in AD, aged control mice performed equally poorly to AD mice on tasks that required memory recall, suggesting that while ‘normal’ aging is associated with decline of memory function, spatial learning is relatively retained compared to AD mice. This finding may inform future research aiming to develop diagnostic tools that will allow clinicians to more comprehensively and efficiently identify patterns of cognitive decline that precede dementia.

A diagnosis of AD is usually made late in the progression of the disease. The extended prodromal stages of AD are generally considered sub-clinical or asymptomatic and any noticeable alterations in cognitive functions or neuropsychiatric status are attributed to normal aging. Earlier identification of abnormal cognitive decline or biomarker irregularities would allow for earlier diagnosis, informing lifestyle changes or novel treatment approaches aimed at reducing risk of progression to AD or delaying the age of clinical onset of this devastating disease.[222]

Author contributions: PD and PLMc both contributed equally to this work, including writing, researching and revising the manuscript.

Conflicts of interest: Some of the data from Denver et al. (2018) has been submitted, in abstract form, to the 2017 Southern California Alzheimer's Disease Centers Research Symposium at the University of California, Beckman Center of the National Academies of Sciences & Engineering, Irvine, CA, USA.

Financial support: This work was supported by the Department of Education and Learning, Northern Ireland.

Copyright license agreement: The Copyright License Agreement has been signed by all authors before publication.

Plagiarism check: Checked twice by iThenticate.

Peer review: Externally peer reviewed.

Open peer reviewers: Nobuyuki Ishibashi, Children's National Health System, USA; Olga Chechneva, University of California, USA.

Additional file: Open peer review reports 1 and 2[Additional file 1].

Funding: This work was supported by the Department of Education and Learning, Northern Ireland, UK.



 
  References Top

1.
Abbas N, Bednar I, Mix E, Marie S, Paterson D, Ljungberg A, Morris C, Winblad B, Nordberg A, Zhu J (2002) Up-regulation of the inflammatory cytokines IFN-gamma and IL-12 and down-regulation of IL-4 in cerebral cortex regions of APP(SWE) transgenic mice. J Neuroimmunol 126:50-57.  Back to cited text no. 1
    
2.
Aizenstein HJ, Nebes RD, Saxton JA, Price JC, Mathis CA, Tsopelas ND, Ziolko SK, James JA, Snitz BE, Houck PR, Bi W, Cohen AD, Lopresti BJ, DeKosky ST, Halligan EM, Klunk WE (2008) Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol 65:1509-1517.  Back to cited text no. 2
    
3.
Alfonso-Loeches S, Urena-Peralta JR, Morillo-Bargues MJ, Oliver-De La Cruz J, Guerri C (2014) Role of mitochondria ROS generation in ethanol-induced NLRP3 inflammasome activation and cell death in astroglial cells. Front Cell Neurosci 8:216.  Back to cited text no. 3
    
4.
Alfonso-Loeches S, Ureña-Peralta J, Morillo-Bargues MJ, Gómez-Pinedo U, Guerri C (2016) Ethanol-induced TLR4/NLRP3 neuroinflammatory response in microglial cells promotes leukocyte infiltration across the BBB. Neurochem Res 41:193-209.  Back to cited text no. 4
    
5.
Allison SL, Fagan AM, Morris JC, Head D (2016) Spatial navigation in preclinical Alzheimer's disease. J Alzheimers Dis 52:77-90.  Back to cited text no. 5
    
6.
Alonso-Nanclares L, Merino-Serrais P, Gonzalez S, DeFelipe J (2013) Synaptic changes in the dentate gyrus of APP/PS1 transgenic mice revealed by electron microscopy. J Neuropathol Exp Neurol 72:386-395.  Back to cited text no. 6
    
7.
Amaral DG, Scharfman HE, Lavenex P (2007) The dentate gyrus: fundamental neuroanatomical organization (dentate gyrus for dummies). Prog Brain Res 163:3-22.  Back to cited text no. 7
    
8.
Andreozzi F, Laratta E, Procopio C, Hribal ML, Sciacqua A, Perticone M, Miele C, Perticone F, Sesti G (2007) Interleukin-6 impairs the insulin signaling pathway, promoting production of nitric oxide in human umbilical vein endothelial cells. Mol Cell Biol 27:2372-2383.  Back to cited text no. 8
    
9.
Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT (1992) Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology 42:631-639.  Back to cited text no. 9
    
10.
Barbieri M, Rizzo MR, Manzella D, Paolisso G (2001) Age-related insulin resistance: is it an obligatory finding? The lesson from healthy centenarians. Diabetes Metab Res Rev 17:19-26.  Back to cited text no. 10
    
11.
Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen M, Soriano F, Vasquez N, Weiss K, Welch B, et al. (2000) Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 6:916-919.  Back to cited text no. 11
    
12.
Barnes CA, Rao G, Shen J (1997) Age-related decrease in the N-methyl-D-aspartateR-mediated excitatory postsynaptic potential in hippocampal region CA1. Neurobiol Aging 18:445-452.  Back to cited text no. 12
    
13.
Barnes DE, Yaffe K (2011) The projected effect of risk factor reduction on Alzheimer's disease prevalence. Lancet Neurol 10:819-828.  Back to cited text no. 13
    
14.
Barreto G, Huang TT, Giffard RG (2010) Age-related defects in sensorimotor activity, spatial learning, and memory in C57BL/6 mice. J Neurosurg Anesthesiol 22:214-219.  Back to cited text no. 14
    
15.
Baumgart M, Snyder HM, Carrillo MC, Fazio S, Kim H, Johns H (2015) Summary of the evidence on modifiable risk factors for cognitive decline and dementia: A population-based perspective. Alzheimers Dement 11:718-726.  Back to cited text no. 15
    
16.
Bizon J, Prescott S, Nicolle MM (2007) Intact spatial learning in adult Tg2576 mice. Neurobiol Aging 28:440-446.  Back to cited text no. 16
    
17.
Blazquez E, Velazquez E, Hurtado-Carneiro V, Ruiz-Albusac JM (2014) Insulin in the brain: its pathophysiological implications for States related with central insulin resistance, type 2 diabetes and Alzheimer's disease. Front Endocrinol (Lausanne) 5:161.  Back to cited text no. 17
    
18.
Bomfim TR, Forny-Germano L, Sathler LB, Brito-Moreira J, Houzel JC, Decker H, Silverman MA, Kazi H, Melo HM, McClean PL, Holscher C, Arnold SE, Talbot K, Klein WL, Munoz DP, Ferreira ST, De Felice FG (2012) An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease-associated Aβ oligomers. J Clin Invest 122:1339-1353.  Back to cited text no. 18
    
19.
Bouet V, Freret T, Dutar P, Billard JM, Boulouard M (2011) Continuous enriched environment improves learning and memory in adult NMRI mice through theta burst-related-LTP independent mechanisms but is not efficient in advanced aged animals. Mech Ageing Dev 132:240-248.  Back to cited text no. 19
    
20.
Boura-Halfon S, Zick Y (2009) Phosphorylation of IRS proteins, insulin action, and insulin resistance. Am J Physiol Endocrinol Metab 296:E581-591.  Back to cited text no. 20
    
21.
Brandt R, Lee G (1993) Functional organization of microtubule-associated protein tau. Identification of regions which affect microtubule growth, nucleation, and bundle formation in vitro. J Biol Chem 268:3414-3419.  Back to cited text no. 21
    
22.
Brodie C, Goldreich N, Haiman T, Kazimirsky G (1998) Functional IL-4 receptors on mouse astrocytes: IL-4 inhibits astrocyte activation and induces NGF secretion. J Neuroimmunol 81:20-30.  Back to cited text no. 22
    
23.
Brosseron F, Krauthausen M, Kummer M, Heneka MT (2014) Body fluid cytokine levels in mild cognitive impairment and Alzheimer's disease: a comparative overview. Mol Neurobiol 50:534-544.  Back to cited text no. 23
    
24.
Browne TC, McQuillan K, McManus RM, O’Reilly JA, Mills KH, Lynch MA (2013) IFN-γ Production by amyloid β-specific Th1 cells promotes microglial activation and increases plaque burden in a mouse model of Alzheimer's disease. J Immunol 190:2241-2251.  Back to cited text no. 24
    
25.
Buckmaster PS, Wenzel HJ, Kunkel DD, Schwartzkroin PA (1996) Axon arbors and synaptic connections of hippocampal mossy cells in the rat in vivo. J Comp Neurol 366:271-292.  Back to cited text no. 25
    
26.
Campuzano O, Castillo-Ruiz MM, Acarin L, Castellano B, Gonzalez B (2009) Increased levels of proinflammatory cytokines in the aged rat brain attenuate injury-induced cytokine response after excitotoxic damage. J Neurosci Res 87:2484-2497.  Back to cited text no. 26
    
27.
Canas PM, Duarte JM, Rodrigues RJ, Kofalvi A, Cunha RA (2009) Modification upon aging of the density of presynaptic modulation systems in the hippocampus. Neurobiol Aging 30:1877-1884.  Back to cited text no. 27
    
28.
Casey DA, Antimisiaris D, O’Brien J (2010) Drugs for Alzheimer's disease: are they effective? P T 35:208-211.  Back to cited text no. 28
    
29.
Castro F, Cardoso AP, Goncalves RM, Serre K, Oliveira MJ (2018) Interferon-gamma at the crossroads of tumor immune surveillance or evasion. Front Immunol 9:847.  Back to cited text no. 29
    
30.
Catalano KJ, Bergman RN, Ader M (2005) Increased susceptibility to insulin resistance associated with abdominal obesity in aging rats. Obes Res 13:11-20.  Back to cited text no. 30
    
31.
Chen G, Chen KS, Kobayashi D, Barbour R, Motter R, Games D, Martin SJ, Morris RG (2007) Active beta-amyloid immunization restores spatial learning in PDAPP mice displaying very low levels of beta-amyloid. J Neurosci 27:2654-2662.  Back to cited text no. 31
    
32.
Cheng D, Low JK, Logge W, Garner B, Karl T (2014) Novel behavioural characteristics of female APPSwe/PS1ΔE9 double transgenic mice. Behav Brain Res 260:111-118.  Back to cited text no. 32
    
33.
Chertkow H, Feldman HH, Jacova C, Massoud F (2013) Definitions of dementia and predementia states in Alzheimer's disease and vascular cognitive impairment: consensus from the Canadian conference on diagnosis of dementia. Alzheimers Res Ther 5:S2.  Back to cited text no. 33
    
34.
Chun W, Johnson GV (2007) The role of tau phosphorylation and cleavage in neuronal cell death. Front Biosci 12:733-756.  Back to cited text no. 34
    
35.
Clare R, King VG, Wirenfeldt M, Vinters HV (2010) Synapse loss in dementias. J Neurosci Res 88:2083-2090.  Back to cited text no. 35
    
36.
Colombo PJ, Gallagher M (2002) Individual differences in spatial memory among aged rats are related to hippocampal PKCgamma immunoreactivity. Hippocampus 12:285-289.  Back to cited text no. 36
    
37.
Coughlan G, Laczo J, Hort J, Minihane AM, Hornberger M (2018) Spatial navigation deficits - overlooked cognitive marker for preclinical Alzheimer disease? Nat Rev Neurol doi: 10.1038/s41582-018-0031-x.  Back to cited text no. 37
    
38.
Counts SE, He B, Nadeem M, Wuu J, Scheff SW, Mufson EJ (2012) Hippocampal drebrin loss in mild cognitive impairment. Neurodegener Dis 10:216-219.  Back to cited text no. 38
    
39.
De-Paula VJ, Radanovic M, Diniz BS, Forlenza OV (2012) Alzheimer's disease. Subcell BiochemDis 65:329-352.  Back to cited text no. 39
    
40.
De Luigi A, Pizzimenti S, Quadri P, Lucca U, Tettamanti M, Fragiacomo C, De Simoni MG (2002) Peripheral inflammatory response in Alzheimer's disease and multiinfarct dementia. Neurobiol Dis 11:308-314.  Back to cited text no. 40
    
41.
Denver P, English A, McClean PL (2018) Inflammation, insulin signaling and cognitive function in aged APP/PS1 mice. Brain Behav Immun 70:423-434.  Back to cited text no. 41
    
42.
Derecki NC, Cardani AN, Yang CH, Quinnies KM, Crihfield A, Lynch KR, Kipnis J (2010) Regulation of learning and memory by meningeal immunity: a key role for IL-4. J Exp Med 207:1067-1080.  Back to cited text no. 42
    
43.
Deupree DL, Bradley J, Turner DA (1993) Age-related alterations in potentiation in the CA1 region in F344 rats. Neurobiol Aging 14:249-258.  Back to cited text no. 43
    
44.
Dilger RN, Johnson RW (2008) Aging, microglial cell priming, and the discordant central inflammatory response to signals from the peripheral immune system. J Leukoc Biol 84:932-939.  Back to cited text no. 44
    
45.
Dineley KT, Westerman M, Bui D, Bell K, Ashe KH, Sweatt JD (2001) Beta-amyloid activates the mitogen-activated protein kinase cascade via hippocampal alpha7 nicotinic acetylcholine receptors: In vitro and in vivo mechanisms related to Alzheimer's disease. J Neurosci 21:4125-4133.  Back to cited text no. 45
    
46.
Dong H, Martin MV, Chambers S, Csernansky JG (2007) Spatial relationship between synapse loss and beta-amyloid deposition in Tg2576 mice. J Comp Neurol 500:311-321.  Back to cited text no. 46
    
47.
Dong X, Zhang L, Meng Q, Gao Q (2017) Association between interleukin-1A, interleukin-1B, and bridging integrator 1 polymorphisms and Alzheimer's disease: a standard and cumulative meta-analysis. Mol Neurobiol 54:736-747.  Back to cited text no. 47
    
48.
Drachman DA (2014) The amyloid hypothesis, time to move on: Amyloid is the downstream result, not cause, of Alzheimer's disease. Alzheimers Dement 10:372-380.  Back to cited text no. 48
    
49.
El-Shimy IA, Heikal OA, Hamdi N (2015) Minocycline attenuates Aβ oligomers-induced pro-inflammatory phenotype in primary microglia while enhancing Aβ fibrils phagocytosis. Neurosci Lett 609:36-41.  Back to cited text no. 49
    
50.
Fath T, Eidenmuller J, Brandt R (2002) Tau-mediated cytotoxicity in a pseudohyperphosphorylation model of Alzheimer's disease. J Neurosci 22:9733-9741.  Back to cited text no. 50
    
51.
Fernandes A, Miller-Fleming L, Pais TF (2014) Microglia and inflammation: conspiracy, controversy or control? Cell Mol Life Sci 71:3969-3985.  Back to cited text no. 51
    
52.
Fernandez-Blazquez MA, Avila-Villanueva M, Maestu F, Medina M (2016) Specific features of subjective cognitive decline predict faster conversion to mild cognitive impairment. J Alzheimers Dis 52:271-281.  Back to cited text no. 52
    
53.
Ferreira ST, Klein WL (2011) The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's disease. Neurobiol Learn Mem 96:529-543.  Back to cited text no. 53
    
54.
Ferreira ST, Lourenco MV, Oliveira MM, De Felice FG (2015) Soluble amyloid-beta oligomers as synaptotoxins leading to cognitive impairment in Alzheimer's disease. Front Cell Neurosci 9:191.  Back to cited text no. 54
    
55.
Ferretti MT, Cuello AC (2011) Does a pro-inflammatory process precede Alzheimer's disease and mild cognitive impairment? Curr Alzheimer Res 8:164-174.  Back to cited text no. 55
    
56.
Fink RI, Kolterman OG, Griffin J, Olefsky JM (1983) Mechanisms of insulin resistance in aging. J Clin Invest 71:1523-1535.  Back to cited text no. 56
    
57.
Fol R, Braudeau J, Ludewig S, Abel T, Weyer SW, Roederer JP, Brod F, Audrain M, Bemelmans AP, Buchholz CJ, Korte M, Cartier N, Muller UC (2016) Viral gene transfer of APPsα rescues synaptic failure in an Alzheimer's disease mouse model. Acta Neuropathol 131:247-266.  Back to cited text no. 57
    
58.
Folstein M, Folstein S (2010) Functional expressions of the aging brain. Nutr Rev 68 Suppl 2:S70-73.  Back to cited text no. 58
    
59.
Forlenza OV, Diniz BS, Talib LL, Mendonça VA, Ojopi EB, Gattaz WF, Teixeira AL (2009) Increased serum IL-1beta level in Alzheimer's disease and mild cognitive impairment. Dement Geriatr Cogn Disord 28:507-512.  Back to cited text no. 59
    
60.
Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia MP, Invidia L, Celani L, Scurti M, Cevenini E, Castellani GC, Salvioli S (2007) Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 128:92-105.  Back to cited text no. 60
    
61.
Frank-Cannon TC, Alto LT, McAlpine FE, Tansey MG (2009) Does neuroinflammation fan the flame in neurodegenerative diseases? Mol Neurodegener 4:47.  Back to cited text no. 61
    
62.
Fricker M, Oliva-Martín MJ, Brown GC (2012) Primary phagocytosis of viable neurons by microglia activated with LPS or Aβ is dependent on calreticulin/LRP phagocytic signalling. J Neuroinflammation 9:196.  Back to cited text no. 62
    
63.
Fu Y, Hsiao JT, Paxinos G, Halliday GM, Kim WS (2016) ABCA7 mediates phagocytic clearance of amyloid-beta in the brain. J Alzheimers Dis 54:569-584.  Back to cited text no. 63
    
64.
Gabuzda D, Yankner BA (2013) Physiology: Inflammation links ageing to the brain. Nature 497:197-198.  Back to cited text no. 64
    
65.
Gadani SP, Cronk JC, Norris GT, Kipnis J (2012) IL-4 in the brain: a cytokine to remember. J Immunol 189:4213-4219.  Back to cited text no. 65
    
66.
Galea E, Morrison W, Hudry E, Arbel-Ornath M, Bacskai BJ, Gómez-Isla T, Stanley HE, Hyman BT (2015) Topological analyses in APP/PS1 mice reveal that astrocytes do not migrate to amyloid-β plaques. Proc Natl Acad Sci U S A 112:15556-15561.  Back to cited text no. 66
    
67.
Gallagher JJ, Minogue AM, Lynch MA (2013) Impaired performance of female APP/PS1 mice in the Morris water maze is coupled with increased Abeta accumulation and microglial activation. Neurodegener Dis 11:33-41.  Back to cited text no. 67
    
68.
Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon MJ, Ye J (2002) Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J Biol Chem 277:48115-48121.  Back to cited text no. 68
    
69.
Gao Z, Zhang X, Zuberi A, Hwang D, Quon MJ, Lefevre M, Ye J (2004) Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes. Mol Endocrinol 18:2024-2034.  Back to cited text no. 69
    
70.
Garcia de Ancos J, Correas I, Avila J (1993) Differences in microtubule binding and self-association abilities of bovine brain tau isoforms. J Biol Chem 268:7976-7982.  Back to cited text no. 70
    
71.
Gee JR, Ding Q, Keller JN (2006) Age-related alterations of Apolipoprotein E and interleukin-1beta in the aging brain. Biogerontology 7:69-79.  Back to cited text no. 71
    
72.
Geinisman Y, Ganeshina O, Yoshida R, Berry RW, Disterhoft JF, Gallagher M (2004) Aging, spatial learning, and total synapse number in the rat CA1 stratum radiatum. Neurobiol Aging 25:407-416.  Back to cited text no. 72
    
73.
Giordano G, Klintworth HM, Kavanagh TJ, Costa LG (2008) Apoptosis induced by domoic acid in mouse cerebellar granule neurons involves activation of p38 and JNK MAP kinases. Neurochem Int 52:1100-1105.  Back to cited text no. 73
    
74.
Godbout JP, Chen J, Abraham J, Richwine AF, Berg BM, Kelley KW, Johnson RW (2005) Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB J 19:1329-1331.  Back to cited text no. 74
    
75.
Griffin R, Nally R, Nolan Y, McCartney Y, Linden J, Lynch MA (2006) The age-related attenuation in long-term potentiation is associated with microglial activation. J Neurochem 99:1263-1272.  Back to cited text no. 75
    
76.
Grundman M, Petersen RC, Ferris SH, Thomas RG, Aisen PS, Bennett DA, Foster NL, Jack CR, Jr., Galasko DR, Doody R, Kaye J, Sano M, Mohs R, Gauthier S, Kim HT, Jin S, Schultz AN, Schafer K, Mulnard R, van Dyck CH, et al. (2004) Mild cognitive impairment can be distinguished from Alzheimer disease and normal aging for clinical trials. Arch Neurol 61:59-66.  Back to cited text no. 76
    
77.
Gulisano W, Maugeri D, Baltrons MA, Fa M, Amato A, Palmeri A, D’Adamio L, Grassi C, Devanand DP, Honig LS, Puzzo D, Arancio O (2018) Role of amyloid-beta and tau proteins in Alzheimer's disease: confuting the amyloid cascade. J Alzheimers Dis 64:S611-s631.  Back to cited text no. 77
    
78.
Guo HB, Cheng YF, Wu JG, Wang CM, Wang HT, Zhang C, Qiu ZK, Xu JP (2015) Donepezil improves learning and memory deficits in APP/PS1 mice by inhibition of microglial activation. Neuroscience 290:530-542.  Back to cited text no. 78
    
79.
Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, Fitzgerald KA, Latz E, Moore KJ, Golenbock DT (2008) The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol 9:857-865.  Back to cited text no. 79
    
80.
Hardy J, Allsop D (1991) Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol Sci 12:383-388.  Back to cited text no. 80
    
81.
Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297:353-356.  Back to cited text no. 81
    
82.
Hardy JA, Higgins GA (1992) Alzheimer's disease: the amyloid cascade hypothesis. Science 256:184-185.  Back to cited text no. 82
    
83.
Harrison FE, Hosseini AH, McDonald MP, May JM (2009) Vitamin C reduces spatial learning deficits in middle-aged and very old APP/PSEN1 transgenic and wild-type mice. Pharmacol Biochem Behav 93:443-450.  Back to cited text no. 83
    
84.
Hatanpaa K, Isaacs KR, Shirao T, Brady DR, Rapoport SI (1999) Loss of proteins regulating synaptic plasticity in normal aging of the human brain and in Alzheimer disease. J Neuropathol Exp Neurol 58:637-643.  Back to cited text no. 84
    
85.
Hedden T, Gabrieli JD (2004) Insights into the ageing mind: a view from cognitive neuroscience. Nat Rev Neurosci 5:87-96.  Back to cited text no. 85
    
86.
Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT (2013) NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature 493:674-678.  Back to cited text no. 86
    
87.
Herrup K (2015) The case for rejecting the amyloid cascade hypothesis. Nat Neurosci 18:794-799.  Back to cited text no. 87
    
88.
Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS (2002) A central role for JNK in obesity and insulin resistance. Nature 420:333-336.  Back to cited text no. 88
    
89.
Hock C, Konietzko U, Streffer JR, Tracy J, Signorell A, Muller-Tillmanns B, Lemke U, Henke K, Moritz E, Garcia E, Wollmer MA, Umbricht D, de Quervain DJ, Hofmann M, Maddalena A, Papassotiropoulos A, Nitsch RM (2003) Antibodies against beta-amyloid slow cognitive decline in Alzheimer's disease. Neuron 38:547-554.  Back to cited text no. 89
    
90.
Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA (2008) Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372:216-223.  Back to cited text no. 90
    
91.
Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, Merry KM, Shi Q, Rosenthal A, Barres BA, Lemere CA, Selkoe DJ, Stevens B (2016) Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352:712-716.  Back to cited text no. 91
    
92.
Hoshino K, Hasegawa K, Kamiya H, Morimoto Y (2017) Synapse-specific effects of IL-1beta on long-term potentiation in the mouse hippocampus. Biomed Res 38:183-188.  Back to cited text no. 92
    
93.
Houtkooper RH, Argmann C, Houten SM, Canto C, Jeninga EH, Andreux PA, Thomas C, Doenlen R, Schoonjans K, Auwerx J (2011) The metabolic footprint of aging in mice. Sci Rep 1:134.  Back to cited text no. 93
    
94.
Hua Y, Guo X, Huang Q, Kong Y, Lu X (2013) Association between interleukin-6 -174G/C polymorphism and the risk of Alzheimer's disease: a meta-analysis. Int J Neurosci 123:626-635.  Back to cited text no. 94
    
95.
Janson J, Laedtke T, Parisi JE, O’Brien P, Petersen RC, Butler PC (2004) Increased risk of type 2 diabetes in Alzheimer disease. Diabetes 53:474-481.  Back to cited text no. 95
    
96.
Jia N, Han K, Kong JJ, Zhang XM, Sha S, Ren GR, Cao YP (2013) (-)-Epigallocatechin-3-gallate alleviates spatial memory impairment in APP/PS1 mice by restoring IRS-1 signaling defects in the hippocampus. Mol Cell Biochem 380:211-218.  Back to cited text no. 96
    
97.
Johnson GV, Stoothoff WH (2004) Tau phosphorylation in neuronal cell function and dysfunction. J Cell Sci 117:5721-5729.  Back to cited text no. 97
    
98.
Kawanokuchi J, Mizuno T, Takeuchi H, Kato H, Wang J, Mitsuma N, Suzumura A (2006) Production of interferon-gamma by microglia. Mult Scler 12:558-564.  Back to cited text no. 98
    
99.
King DL, Arendash GW (2002) Maintained synaptophysin immunoreactivity in Tg2576 transgenic mice during aging: correlations with cognitive impairment. Brain Res 926:58-68.  Back to cited text no. 99
    
100.
Klein WL, Krafft GA, Finch CE (2001) Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum? Trends Neurosci 24:219-224.  Back to cited text no. 100
    
101.
Koenigsknecht J, Landreth G (2004) Microglial phagocytosis of fibrillar beta-amyloid through a beta1 integrin-dependent mechanism. J Neurosci 24:9838-9846.  Back to cited text no. 101
    
102.
Koistinaho M, Lin S, Wu X, Esterman M, Koger D, Hanson J, Higgs R, Liu F, Malkani S, Bales KR, Paul SM (2004) Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides. Nat Med 10:719-726.  Back to cited text no. 102
    
103.
Kokjohn TA, Roher AE (2009) Antibody responses, amyloid-beta peptide remnants and clinical effects of AN-1792 immunization in patients with AD in an interrupted trial. CNS Neurol Disord Drug Targets 8:88-97.  Back to cited text no. 103
    
104.
Kotilinek LA, Bacskai B, Westerman M, Kawarabayashi T, Younkin L, Hyman BT, Younkin S, Ashe KH (2002) Reversible memory loss in a mouse transgenic model of Alzheimer's disease. J Neurosci 22:6331-6335.  Back to cited text no. 104
    
105.
Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312-318.  Back to cited text no. 105
    
106.
Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL (1998) Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A 95:6448-6453.  Back to cited text no. 106
    
107.
Latta CH, Sudduth TL, Weekman EM, Brothers HM, Abner EL, Popa GJ, Mendenhall MD, Gonzalez-Oregon F, Braun K, Wilcock DM (2015) Determining the role of IL-4 induced neuroinflammation in microglial activity and amyloid-beta using BV2 microglial cells and APP/PS1 transgenic mice. J Neuroinflammation 12:41.  Back to cited text no. 107
    
108.
Lau LT, Yu AC (2001) Astrocytes produce and release interleukin-1, interleukin-6, tumor necrosis factor alpha and interferon-gamma following traumatic and metabolic injur. J Neurotrauma 18:351-359.  Back to cited text no. 108
    
109.
Lee CY, Landreth GE (2010) The role of microglia in amyloid clearance from the AD brain. J Neural Transm (Vienna) 117:949-960.  Back to cited text no. 109
    
110.
Lee HJ, Park HJ, Starkweather A, An K, Shim I (2016) Decreased interleukin-4 release from the neurons of the locus coeruleus in response to immobilization stress. Mediators Inflamm 2016:3501905.  Back to cited text no. 110
    
111.
Leszek J, Barreto GE, Gasiorowski K, Koutsouraki E, Avila-Rodrigues M, Aliev G (2016) Inflammatory mechanisms and oxidative stress as key factors responsible for progression of neurodegeneration: role of brain innate immune system. CNS Neurol Disord Drug Targets 15:329-336.  Back to cited text no. 111
    
112.
Li F, Wei G, Bai Y, Li Y, Huang F, Lin J, Hou Q, Deng R, Zhou JH, Zhang SX, Chen DF (2015) MicroRNA-574 is involved in cognitive impairment in 5-month-old APP/PS1 mice through regulation of neuritin. Brain Res 1627:177-188.  Back to cited text no. 112
    
113.
Licastro F, Porcellini E, Caruso C, Lio D, Corder EH (2007) Genetic risk profiles for Alzheimer's disease: integration of APOE genotype and variants that up-regulate inflammation. Neurobiol Aging 28:1637-1643.  Back to cited text no. 113
    
114.
Lipina C, Vaanholt LM, Davidova A, Mitchell SE, Storey-Gordon E, Hambly C, Irving AJ, Speakman JR, Hundal HS (2016) CB1 receptor blockade counters age-induced insulin resistance and metabolic dysfunction. Aging Cell 15:325-335.  Back to cited text no. 114
    
115.
Lithfous S, Dufour A, Despres O (2013) Spatial navigation in normal aging and the prodromal stage of Alzheimer's disease: insights from imaging and behavioral studies. Ageing Res Rev 12:201-213.  Back to cited text no. 115
    
116.
Liu H, Prayson RA, Estes ML, Drazba JA, Barnett GH, Bingaman W, Liu J, Jacobs BS, Barna BP (2000) In vivo expression of the interleukin 4 receptor alpha by astrocytes in epilepsy cerebral cortex. Cytokine 12:1656-1661.  Back to cited text no. 116
    
117.
Liu SJ, Yang C, Zhang Y, Su RY, Chen JL, Jiao MM, Chen HF, Zheng N, Luo S, Chen YB, Quan SJ, Wang Q (2016) Neuroprotective effect of β-asarone against Alzheimer's disease: regulation of synaptic plasticity by increased expression of SYP and GluR1. Drug Des Devel Ther 10:1461-1469.  Back to cited text no. 117
    
118.
Liu Y, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX (2011) Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes. J Pathol 225:54-62.  Back to cited text no. 118
    
119.
Long LH, Liu RL, Wang F, Liu J, Hu ZL, Xie N, Jin Y, Fu H, Chen JG (2009) Age-related synaptic changes in the CA1 stratum radiatum and spatial learning impairment in rats. Clin Exp Pharmacol Physiol 36:675-681.  Back to cited text no. 119
    
120.
Lontchi-Yimagou E, Sobngwi E, Matsha TE, Kengne AP (2013) Diabetes mellitus and inflammation. Curr Diab Rep 13:435-444.  Back to cited text no. 120
    
121.
Lord A, Englund H, Soderberg L, Tucker S, Clausen F, Hillered L, Gordon M, Morgan D, Lannfelt L, Pettersson FE, Nilsson LN (2009) Amyloid-beta protofibril levels correlate with spatial learning in Arctic Alzheimer's disease transgenic mice. FEBS J 276:995-1006.  Back to cited text no. 121
    
122.
Lu Q, Wood JG (1993) Functional studies of Alzheimer's disease tau protein. J Neurosci 13:508-515.  Back to cited text no. 122
    
123.
Lull ME, Block ML (2010) Microglial activation and chronic neurodegeneration. Neurotherapeutics 7:354-365.  Back to cited text no. 123
    
124.
Luzina IG, Keegan AD, Heller NM, Rook GA, Shea-Donohue T, Atamas SP (2012) Regulation of inflammation by interleukin-4: a review of “alternatives”. J Leukoc Biol 92:753-764.  Back to cited text no. 124
    
125.
Lynch MA (2010) Age-related neuroinflammatory changes negatively impact on neuronal function. Front Aging Neurosci 1:6.  Back to cited text no. 125
    
126.
Maher FO, Martin DS, Lynch MA (2004) Increased IL-1beta in cortex of aged rats is accompanied by downregulation of ERK and PI-3 kinase. Neurobiol Aging 25:795-806.  Back to cited text no. 126
    
127.
Malek-Ahmadi M, Perez SE, Chen K, Mufson EJ (2016) Neuritic and diffuse plaque associations with memory in non-cognitively impaired elderly. J Alzheimers Dis 53:1641-1652.  Back to cited text no. 127
    
128.
Malthankar-Phatak GH, Lin YG, Giovannone N, Siman R (2012) Amyloid deposition and advanced age fails to induce Alzheimer's type progression in a double knock-in mouse model. Aging Dis 3:141-155.  Back to cited text no. 128
    
129.
Mandrekar S, Jiang Q, Lee CY, Koenigsknecht-Talboo J, Holtzman DM, Landreth GE (2009) Microglia mediate the clearance of soluble Abeta through fluid phase macropinocytosis. J Neurosci 29:4252-4262.  Back to cited text no. 129
    
130.
Matt SM, Johnson RW (2016) Neuro-immune dysfunction during brain aging: new insights in microglial cell regulation. Curr Opin Pharmacol 26:96-101.  Back to cited text no. 130
    
131.
McAfoose J, Baune BT (2009) Evidence for a cytokine model of cognitive function. Neurosci Biobehav Rev 33:355-366.  Back to cited text no. 131
    
132.
McClean PL, Parthsarathy V, Faivre E, Holscher C (2011) The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease. J Neurosci 31:6587-6594.  Back to cited text no. 132
    
133.
McGeer PL, McGeer EG (2013) The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy. Acta Neuropathol 126:479-497.  Back to cited text no. 133
    
134.
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Jr., Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH (2011) The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 7:263-269.  Back to cited text no. 134
    
135.
Menard C, Quirion R (2012) Successful cognitive aging in rats: a role for mGluR5 glutamate receptors, homer 1 proteins and downstream signaling pathways. PLoS One 7:e28666.  Back to cited text no. 135
    
136.
Meraz-Rios MA, Toral-Rios D, Franco-Bocanegra D, Villeda-Hernandez J, Campos-Pena V (2013) Inflammatory process in Alzheimer's Disease. Front Integr Neurosci 7:59.  Back to cited text no. 136
    
137.
Minkeviciene R, Ihalainen J, Malm T, Matilainen O, Keksa-Goldsteine V, Goldsteins G, Iivonen H, Leguit N, Glennon J, Koistinaho J, Banerjee P, Tanila H (2008) Age-related decrease in stimulated glutamate release and vesicular glutamate transporters in APP/PS1 transgenic and wild-type mice. J Neurochem 105:584-594.  Back to cited text no. 137
    
138.
Mittal K, Katare DP (2016) Shared links between type 2 diabetes mellitus and Alzheimer's disease: A review. Diabetes Metab Syndr 10:S144-149.  Back to cited text no. 138
    
139.
Moloney AM, Griffin RJ, Timmons S, O’Connor R, Ravid R, O’Neill C (2010) Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer's disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol Aging 31:224-243.  Back to cited text no. 139
    
140.
Morellini F, Sivukhina E, Stoenica L, Oulianova E, Bukalo O, Jakovcevski I, Dityatev A, Irintchev A, Schachner M (2010) Improved reversal learning and working memory and enhanced reactivity to novelty in mice with enhanced GABAergic innervation in the dentate gyrus. Cereb Cortex 20:2712-2727.  Back to cited text no. 140
    
141.
Mrak RE, Griffin WS (2001) Interleukin-1, neuroinflammation, and Alzheimer's disease. Neurobiol Aging 22:903-908.  Back to cited text no. 141
    
142.
Murray CJ, Richards MA, Newton JN, Fenton KA, Anderson HR, Atkinson C, Bennett D, Bernabe E, Blencowe H, Bourne R, Braithwaite T, Brayne C, Bruce NG, Brugha TS, Burney P, Dherani M, Dolk H, Edmond K, Ezzati M, Flaxman AD, et al. (2013) UK health performance: findings of the Global Burden of Disease Study 2010. Lancet 381:997-1020.  Back to cited text no. 142
    
143.
Musiek ES, Holtzman DM (2015) Three dimensions of the amyloid hypothesis: time, space and ‘wingmen’. Nat Neurosci 18:800-806.  Back to cited text no. 143
    
144.
Myers CE, Scharfman HE (2011) Pattern separation in the dentate gyrus: a role for the CA3 backprojection. Hippocampus 21:1190-1215.  Back to cited text no. 144
    
145.
Nagele RG, D’Andrea MR, Lee H, Venkataraman V, Wang HY (2003) Astrocytes accumulate A beta 42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains. Brain Res 971:197-209.  Back to cited text no. 145
    
146.
Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, Castellani RJ, Crain BJ, Davies P, Del Tredici K, Duyckaerts C, Frosch MP, Haroutunian V, Hof PR, Hulette CM, Hyman BT, Iwatsubo T, Jellinger KA, Jicha GA, Kovari E, et al. (2012) Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol 71:362-381.  Back to cited text no. 146
    
147.
Neniskyte U, Neher JJ, Brown GC (2011) Neuronal death induced by nanomolar amyloid beta is mediated by primary phagocytosis of neurons by microglia. J Biol Chem 286:39904-39913.  Back to cited text no. 147
    
148.
Neniskyte U, Fricker M, Brown GC (2016) Amyloid β induces microglia to phagocytose neurons via activation of protein kinase Cs and NADPH oxidase. Int J Biochem Cell Biol 81:346-355.  Back to cited text no. 148
    
149.
Neuman KM, Molina-Campos E, Musial TF, Price AL, Oh KJ, Wolke ML, Buss EW, Scheff SW, Mufson EJ, Nicholson DA (2015) Evidence for Alzheimer's disease-linked synapse loss and compensation in mouse and human hippocampal CA1 pyramidal neurons. Brain Struct Funct 220:3143-3165.  Back to cited text no. 149
    
150.
Nicholson DA, Yoshida R, Berry RW, Gallagher M, Geinisman Y (2004) Reduction in size of perforated postsynaptic densities in hippocampal axospinous synapses and age-related spatial learning impairments. J Neurosci 24:7648-7653.  Back to cited text no. 150
    
151.
Norden DM, Godbout JP (2013) Review: microglia of the aged brain: primed to be activated and resistant to regulation. Neuropathol Appl Neurobiol 39:19-34.  Back to cited text no. 151
    
152.
Norden DM, Muccigrosso MM, Godbout JP (2015) Microglial priming and enhanced reactivity to secondary insult in aging, and traumatic CNS injury, and neurodegenerative disease. Neuropharmacology 96:29-41.  Back to cited text no. 152
    
153.
Nyffeler M, Zhang WN, Feldon J, Knuesel I (2007) Differential expression of PSD proteins in age-related spatial learning impairments. Neurobiol Aging 28:143-155.  Back to cited text no. 153
    
154.
O’Reilly JA, Lynch M (2012) Rosiglitazone improves spatial memory and decreases insoluble Aβ(1-42) in APP/PS1 mice. J Neuroimmune Pharmacol 7:140-144.  Back to cited text no. 154
    
155.
Ostapchenko VG, Chen M, Guzman MS, Xie YF, Lavine N, Fan J, Beraldo FH, Martyn AC, Belrose JC, Mori Y, MacDonald JF, Prado VF, Prado MA, Jackson MF (2015) The transient receptor potential melastatin 2 (TRPM2) channel contributes to beta-amyloid oligomer-related neurotoxicity and memory impairment. J Neurosci 35:15157-15169.  Back to cited text no. 155
    
156.
Panda D, Goode BL, Feinstein SC, Wilson L (1995) Kinetic stabilization of microtubule dynamics at steady state by tau and microtubule-binding domains of tau. Biochemistry 34:11117-11127.  Back to cited text no. 156
    
157.
Paolisso G, Tagliamonte MR, Rizzo MR, Giugliano D (1999) Advancing age and insulin resistance: new facts about an ancient history. Eur J Clin Invest 29:758-769.  Back to cited text no. 157
    
158.
Parajuli B, Sonobe Y, Horiuchi H, Takeuchi H, Mizuno T, Suzumura A (2013) Oligomeric amyloid β induces IL-1β processing via production of ROS: implication in Alzheimer's disease. Cell Death Dis 4:e975.  Back to cited text no. 158
    
159.
Park D, Lee EK, Jang EJ, Jeong HO, Kim BC, Ha YM, Hong SE, Yu BP, Chung HY (2013) Identification of the dichotomous role of age-related LCK in calorie restriction revealed by integrative analysis of cDNA microarray and interactome. Age (Dordr) 35:1045-1060.  Back to cited text no. 159
    
160.
Patel NS, Paris D, Mathura V, Quadros AN, Crawford FC, Mullan MJ (2005) Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer's disease. J Neuroinflammation 2:9.  Back to cited text no. 160
    
161.
Perry VH (2004) The influence of systemic inflammation on inflammation in the brain: implications for chronic neurodegenerative disease. Brain Behav Immun 18:407-413.  Back to cited text no. 161
    
162.
Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E (1999) Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 56:303-308.  Back to cited text no. 162
    
163.
Portbury SD, Hare DJ, Sgambelloni C, Perronnes K, Portbury AJ, Finkelstein DI, Adlard PA (2017) Trehalose improves cognition in the transgenic Tg2576 mouse model of Alzheimer's disease. J Alzheimers Dis 60:549-560.  Back to cited text no. 163
    
164.
Price JL, Morris JC (1999) Tangles and plaques in nondemented aging and “preclinical” Alzheimer's disease. Ann Neurol 45:358-368.  Back to cited text no. 164
    
165.
Price JL, Davis PB, Morris JC, White DL (1991) The distribution of tangles, plaques and related immunohistochemical markers in healthy aging and Alzheimer's disease. Neurobiol Aging 12:295-312.  Back to cited text no. 165
    
166.
Prieto GA, Tong L, Smith ED, Cotman CW (2018) TNFα and IL-1β but not IL-18 suppresses hippocampal long-term potentiation directly at the synapse. Neurochem Res doi: 10.1007/s11064-018-2517-8.  Back to cited text no. 166
    
167.
Querfurth HW, LaFerla FM (2010) Alzheimer's disease. N Engl J Med 362:329-344.  Back to cited text no. 167
    
168.
Rabin LA, Smart CM, Amariglio RE (2017) Subjective Cognitive Decline in Preclinical Alzheimer's Disease. Annu Rev Clin Psychol 13:369-396.  Back to cited text no. 168
    
169.
Reitz C, Mayeux R (2014) Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem Pharmacol 88:640-651.  Back to cited text no. 169
    
170.
Rezai-Zadeh K, Gate D, Town T (2009) CNS infiltration of peripheral immune cells: D-Day for neurodegenerative disease? J Neuroimmune Pharmacol 4:462-475.  Back to cited text no. 170
    
171.
Rizzi L, Rosset I, Roriz-Cruz M (2014) Global epidemiology of dementia: Alzheimer's and vascular types. Biomed Res Int 2014:908915.  Back to cited text no. 171
    
172.
Robinson JL, Molina-Porcel L, Corrada MM, Raible K, Lee EB, Lee VM, Kawas CH, Trojanowski JQ (2014) Perforant path synaptic loss correlates with cognitive impairment and Alzheimer's disease in the oldest-old. Brain 137:2578-2587.  Back to cited text no. 172
    
173.
Rogers J, Lue LF (2001) Microglial chemotaxis, activation, and phagocytosis of amyloid beta-peptide as linked phenomena in Alzheimer's disease. Neurochem Int 39:333-340.  Back to cited text no. 173
    
174.
Romanatto T, Fiamoncini J, Wang B, Curi R, Kang JX (2014) Elevated tissue omega-3 fatty acid status prevents age-related glucose intolerance in fat-1 transgenic mice. Biochim Biophys Acta 1842:186-191.  Back to cited text no. 174
    
175.
Rowe JW, Minaker KL, Pallotta JA, Flier JS (1983) Characterization of the insulin resistance of aging. J Clin Invest 71:1581-1587.  Back to cited text no. 175
    
176.
Sa Q, Ochiai E, Tiwari A, Perkins S, Mullins J, Gehman M, Huckle W, Eyestone WH, Saunders TL, Shelton BJ, Suzuki Y (2015) Cutting edge: IFN-gamma produced by brain-resident cells is crucial to control cerebral infection with Toxoplasma gondii. J Immunol 195:796-800.  Back to cited text no. 176
    
177.
Salminen A, Ojala J, Suuronen T, Kaarniranta K, Kauppinen A (2008) Amyloid-beta oligomers set fire to inflammasomes and induce Alzheimer's pathology. J Cell Mol Med 12:2255-2262.  Back to cited text no. 177
    
178.
Savva GM, Wharton SB, Ince PG, Forster G, Matthews FE, Brayne C (2009) Age, neuropathology, and dementia. N Engl J Med 360:2302-2309.  Back to cited text no. 178
    
179.
Scharfman HE (1995) Electrophysiological evidence that dentate hilar mossy cells are excitatory and innervate both granule cells and interneurons. J Neurophysiol 74:179-194.  Back to cited text no. 179
    
180.
Scharfman HE, Myers CE (2012) Hilar mossy cells of the dentate gyrus: a historical perspective. Front Neural Circuits 6:106.  Back to cited text no. 180
    
181.
Scheff SW, Price DA (1998) Synaptic density in the inner molecular layer of the hippocampal dentate gyrus in Alzheimer disease. J Neuropathol Exp Neurol 57:1146-1153.  Back to cited text no. 181
    
182.
Scheff SW, Sparks DL, Price DA (1996) Quantitative assessment of synaptic density in the outer molecular layer of the hippocampal dentate gyrus in Alzheimer's disease. Dementia 7:226-232.  Back to cited text no. 182
    
183.
Schilling M, Besselmann M, Leonhard C, Mueller M, Ringelstein EB, Kiefer R (2003) Microglial activation precedes and predominates over macrophage infiltration in transient focal cerebral ischemia: a study in green fluorescent protein transgenic bone marrow chimeric mice. Exp Neurol 183:25-33.  Back to cited text no. 183
    
184.
Shaftel SS, Griffin WS, O’Banion MK (2008) The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective. J Neuroinflammation 5:7.  Back to cited text no. 184
    
185.
Shankar GM, Walsh DM (2009) Alzheimer's disease: synaptic dysfunction and Abeta. Mol Neurodegener 4:48.  Back to cited text no. 185
    
186.
Shi XD, Sun K, Hu R, Liu XY, Hu QM, Sun XY, Yao B, Sun N, Hao JR, Wei P, Han Y, Gao C (2016) Blocking the Interaction between EphB2 and ADDLs by a small peptide rescues impaired synaptic plasticity and memory deficits in a mouse model of Alzheimer's disease. J Neurosci 36:11959-11973.  Back to cited text no. 186
    
187.
Shoji H, Takao K, Hattori S, Miyakawa T (2016) Age-related changes in behavior in C57BL/6J mice from young adulthood to middle age. Mol Brain 9:11.  Back to cited text no. 187
    
188.
Siddle K (2011) Signalling by insulin and IGF receptors: supporting acts and new players. J Mol Endocrinol 47:R1-10.  Back to cited text no. 188
    
189.
Spangenberg EE, Lee RJ, Najafi AR, Rice RA, Elmore MR, Blurton-Jones M, West BL, Green KN (2016) Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-β pathology. Brain 139:1265-1281.  Back to cited text no. 189
    
190.
Steardo L Jr, Bronzuoli MR, Iacomino A, Esposito G, Steardo L, Scuderi C (2015) Does neuroinflammation turn on the flame in Alzheimer's disease? Focus on astrocytes. Front Neurosci 9:259.  Back to cited text no. 190
    
191.
Stover KR, Campbell MA, Van Winssen CM, Brown RE (2015) Early detection of cognitive deficits in the 3xTg-AD mouse model of Alzheimer's disease. Behav Brain Res 289:29-38.  Back to cited text no. 191
    
192.
Swerdlow RH (2011) Brain aging, Alzheimer's disease, and mitochondria. Biochim Biophys Acta 1812:1630-1639.  Back to cited text no. 192
    
193.
Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A, Fuino RL, Kawaguchi KR, Samoyedny AJ, Wilson RS, Arvanitakis Z, Schneider JA, Wolf BA, Bennett DA, Trojanowski JQ, Arnold SE (2012) Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest 122:1316-1338.  Back to cited text no. 193
    
194.
Tannenberg RK, Scott HL, Tannenberg AE, Dodd PR (2006) Selective loss of synaptic proteins in Alzheimer's disease: evidence for an increased severity with APOE varepsilon4. Neurochem Int 49:631-639.  Back to cited text no. 194
    
195.
Tarkowski E, Andreasen N, Tarkowski A, Blennow K (2003) Intrathecal inflammation precedes development of Alzheimer's disease. J Neurol Neurosurg Psychiatry 74:1200-1205.  Back to cited text no. 195
    
196.
Taylor R (2012) Insulin resistance and type 2 diabetes. Diabetes 61:778-779.  Back to cited text no. 196
    
197.
Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572-580.  Back to cited text no. 197
    
198.
Tha KK, Okuma Y, Miyazaki H, Murayama T, Uehara T, Hatakeyama R, Hayashi Y, Nomura Y (2000) Changes in expressions of proinflammatory cytokines IL-1beta, TNF-alpha and IL-6 in the brain of senescence accelerated mouse (SAM) P8. Brain Res 885:25-31.  Back to cited text no. 198
    
199.
Tiernan CT, Mufson EJ, Kanaan NM, Counts SE (2018) Tau oligomer pathology in nucleus basalis neurons during the progression of Alzheimer disease. J Neuropathol Exp Neurol 77:246-259.  Back to cited text no. 199
    
200.
Timonin S, Shkolnikov VM, Jasilionis D, Grigoriev P, Jdanov DA, Leon DA (2016) Disparities in length of life across developed countries: measuring and decomposing changes over time within and between country groups. Popul Health Metr 14:29.  Back to cited text no. 200
    
201.
Tuppo EE, Arias HR (2005) The role of inflammation in Alzheimer's disease. Int J Biochem Cell Biol 37:289-305.  Back to cited text no. 201
    
202.
Vana L, Kanaan NM, Ugwu IC, Wuu J, Mufson EJ, Binder LI (2011) Progression of tau pathology in cholinergic Basal forebrain neurons in mild cognitive impairment and Alzheimer's disease. Am J Pathol 179:2533-2550.  Back to cited text no. 202
    
203.
VanGuilder HD, Yan H, Farley JA, Sonntag WE, Freeman WM (2010) Aging alters the expression of neurotransmission-regulating proteins in the hippocampal synaptoproteome. J Neurochem 113:1577-1588.  Back to cited text no. 203
    
204.
Vereker E, O’Donnell E, Lynch MA (2000) The inhibitory effect of interleukin-1beta on long-term potentiation is coupled with increased activity of stress-activated protein kinases. J Neurosci 20:6811-6819.  Back to cited text no. 204
    
205.
Wang X, Suzuki Y (2007) Microglia produce IFN-gamma independently from T cells during acute toxoplasmosis in the brain. J Interferon Cytokine Res 27:599-605.  Back to cited text no. 205
    
206.
Wendeln AC, Degenhardt K, Kaurani L, Gertig M, Ulas T, Jain G, Wagner J, Häsler LM, Wild K, Skodras A, Blank T, Staszewski O, Datta M, Centeno TP, Capece V, Islam MR, Kerimoglu C, Staufenbiel M, Schultze JL, Beyer M, et al. (2018) Innate immune memory in the brain shapes neurological disease hallmarks. Nature 556:332-338.  Back to cited text no. 206
    
207.
White MF (2003) Insulin signaling in health and disease. Science 302:1710-1711.  Back to cited text no. 207
    
208.
Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund LO, Nordberg A, Backman L, Albert M, Almkvist O, Arai H, Basun H, Blennow K, de Leon M, DeCarli C, Erkinjuntti T, Giacobini E, Graff C, Hardy J, Jack C, et al. (2004) Mild cognitive impairment--beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med 256:240-246.  Back to cited text no. 208
    
209.
Wolf A, Bauer B, Abner EL, Ashkenazy-Frolinger T, Hartz AM (2016) A comprehensive behavioral test battery to assess learning and memory in 129S6/Tg2576 mice. PLoS One 11:e0147733.  Back to cited text no. 209
    
210.
Wright AL, Zinn R, Hohensinn B, Konen LM, Beynon SB, Tan RP, Clark IA, Abdipranoto A, Vissel B (2013) Neuroinflammation and neuronal loss precede Abeta plaque deposition in the hAPP-J20 mouse model of Alzheimer's disease. PLoS One 8:e59586.  Back to cited text no. 210
    
211.
Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, Silverstein SC, Husemann J (2003) Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat Med 9:453-457.  Back to cited text no. 211
    
212.
Xiao Q, Shi R, Yang W, Zou Y, Du Y, Zhang M, Yu W, Lu Y (2016) Time-dependent increase of chitinase1 in APP/PS1 double transgenic mice. Neurochem Res 41:1604-1611.  Back to cited text no. 212
    
213.
Xuan AG, Pan XB, Wei P, Ji WD, Zhang WJ, Liu JH, Hong LP, Chen WL, Long DH (2015) Valproic acid alleviates memory deficits and attenuates amyloid-beta deposition in transgenic mouse model of Alzheimer's disease. Mol Neurobiol 51:300-312.  Back to cited text no. 213
    
214.
Yamamoto M, Otsuki M (2006) Effect of inhibition of alpha-glucosidase on age-related glucose intolerance and pancreatic atrophy in rats. Metabolism 55:533-540.  Back to cited text no. 214
    
215.
Yan JJ, Jung JS, Kim TK, Hasan A, Hong CW, Nam JS, Song DK (2013) Protective effects of ferulic acid in amyloid precursor protein plus presenilin-1 transgenic mouse model of Alzheimer disease. Biol Pharm Bull 36:140-143.  Back to cited text no. 215
    
216.
Ye SM, Johnson RW (1999) Increased interleukin-6 expression by microglia from brain of aged mice. J Neuroimmunol 93:139-148.  Back to cited text no. 216
    
217.
Zhang MY, Zheng CY, Zou MM, Zhu JW, Zhang Y, Wang J, Liu CF, Li QF, Xiao ZC, Li S, Ma QH, Xu RX (2014) Lamotrigine attenuates deficits in synaptic plasticity and accumulation of amyloid plaques in APP/PS1 transgenic mice. Neurobiol Aging 35:2713-2725.  Back to cited text no. 217
    
218.
Zhang Y, Huang LJ, Shi S, Xu SF, Wang XL, Peng Y (2016) L-3-n-butylphthalide rescues hippocampal synaptic failure and attenuates neuropathology in aged APP/PS1 mouse model of Alzheimer's disease. CNS Neurosci Ther 22:979-987.  Back to cited text no. 218
    
219.
Zhang Y, Zhang J, Tian C, Xiao Y, Li X, He C, Huang J, Fan H (2011) The -1082G/A polymorphism in IL-10 gene is associated with risk of Alzheimer's disease: a meta-analysis. J Neurol Sci 303:133-138.  Back to cited text no. 219
    
220.
Zhao WQ, De Felice FG, Fernandez S, Chen H, Lambert MP, Quon MJ, Krafft GA, Klein WL (2008) Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J 22:246-260.  Back to cited text no. 220
    
221.
Zhao X, Wang H, Sun G, Zhang J, Edwards NJ, Aronowski J (2015) Neuronal interleukin-4 as a modulator of microglial pathways and ischemic brain damage. J Neurosci 35:11281-11291.  Back to cited text no. 221
    
222.
Zheng C, Zhou XW, Wang JZ (2016) The dual roles of cytokines in Alzheimer's disease: update on interleukins, TNF-α, TGF-β and IFN-γ. Transl Neurodegener 5:7.  Back to cited text no. 222
    



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