Microglial dysfunction in brain aging and Alzheimer's disease

Mosher, Kira Irving; Wyss‐Coray, Tony

doi:10.1016/j.bcp.2014.01.008

Cited by 492 publications

(430 citation statements)

References 151 publications

(165 reference statements)

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“…Converging evidence indicates that the aged brain contains primed and/or senescent microglia (Dilger & Johnson, 2008; Harry, 2013; Mosher & Wyss‐Coray, 2014), which may contribute to age‐related cognitive deficits and altered brain function (Norden et al, 2015). Therefore, we sought to explore the effects of replacing these resident “aged" microglia with new cells, via administration and withdrawal of CSF1R inhibitors.…”

Section: Resultsmentioning

confidence: 99%

“…Microglial activation is a hallmark of aging and studies have shown that microglial phenotype and function are altered in the aged brain [reviewed in (Mosher & Wyss‐Coray, 2014)]. To explore how the replacement of aged microglia with new cells affects and shapes the resultant tissue, we employed a method of CSF1R inhibitor‐induced microglial elimination and repopulation.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, microglial elimination and repopulation may be beneficial in situations that implicate altered microglial phenotypes in impaired brain function. During aging, microglia undergo marked phenotypic and functional changes compared to the adult brain, including increased cell numbers, dystrophic morphology, impaired phagocytosis, reduced motility, exaggerated response to inflammatory stimuli [reviewed in Mosher and Wyss‐Coray (2014)], as well as altered gene expression (Galatro et al, 2017; Grabert et al, 2016; Soreq, Rose, Soreq, Hardy, & Ule, 2017). These microglia are often described as “primed” or “senescent,” and recent studies suggest that these cells may contribute to age‐related cognitive impairments and confer susceptibility to neurodegenerative disease (Blank & Prinz, 2013; Niraula, Sheridan, & Godbout, 2017; Norden, Muccigrosso, & Godbout, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

et al. 2018

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Microglia, the resident immune cell of the brain, can be eliminated via pharmacological inhibition of the colony‐stimulating factor 1 receptor (CSF1R). Withdrawal of CSF1R inhibition then stimulates microglial repopulation, effectively replacing the microglial compartment. In the aged brain, microglia take on a “primed” phenotype and studies indicate that this coincides with age‐related cognitive decline. Here, we investigated the effects of replacing the aged microglial compartment with new microglia using CSF1R inhibitor‐induced microglial repopulation. With 28 days of repopulation, replacement of resident microglia in aged mice (24 months) improved spatial memory and restored physical microglial tissue characteristics (cell densities and morphologies) to those found in young adult animals (4 months). However, inflammation‐related gene expression was not broadly altered with repopulation nor the response to immune challenges. Instead, microglial repopulation resulted in a reversal of age‐related changes in neuronal gene expression, including expression of genes associated with actin cytoskeleton remodeling and synaptogenesis. Age‐related changes in hippocampal neuronal complexity were reversed with both microglial elimination and repopulation, while microglial elimination increased both neurogenesis and dendritic spine densities. These changes were accompanied by a full rescue of age‐induced deficits in long‐term potentiation with microglial repopulation. Thus, several key aspects of the aged brain can be reversed by acute noninvasive replacement of microglia.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

et al. 2018

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“…While there have been some reports on each glia type in AD pathogenesis, astrocytes, which constitute approximately 30% of cells in the mammalian central nervous system, and oligodendrocytes, are hardly studied in the aging process. Brain aging includes proinflammatory phenotypes, altered signaling, and accumulation of senescent microglia (Harry, 2013; Mosher & Wyss‐Coray, 2014). Abnormalities in microglial cytoplasmic structure were observed in a case study of two nondemented subjects (one 68‐year‐old and one 38‐year‐old) were defined as microglial dystrophy which was further concluded as a sign of microglial cell senescence (Streit, Sammons, Kuhns, & Sparks, 2004).…”

Section: Cellular Changes In Aging and Admentioning

confidence: 99%

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

et al. 2018

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Alzheimer's disease is the most prevalent cause of dementia, which is defined by the combined presence of amyloid and tau, but researchers are gradually moving away from the simple assumption of linear causality proposed by the original amyloid hypothesis. Aging is the main risk factor for Alzheimer's disease that cannot be explained by amyloid hypothesis. To evaluate how aging and Alzheimer's disease are intrinsically interwoven with each other, we review and summarize evidence from molecular, cellular, and system level. In particular, we focus on study designs, treatments, or interventions in Alzheimer's disease that could also be insightful in aging and vice versa.

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“…Initially, microglia respond to and surround plaques, degrading Aβ by phagocytosis (for review, see refs. [6][7][8]. However, chronic activation of these cells shift microglia to a more proinflammatory and less phagocytic state (9,10).…”

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confidence: 99%

The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

Marsh

Abud

Lakatos

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

334

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The innate immune system is strongly implicated in the pathogenesis of Alzheimer's disease (AD). In contrast, the role of adaptive immunity in AD remains largely unknown. However, numerous clinical trials are testing vaccination strategies for AD, suggesting that T and B cells play a pivotal role in this disease. To test the hypothesis that adaptive immunity influences AD pathogenesis, we generated an immune-deficient AD mouse model that lacks T, B, and natural killer (NK) cells. The resulting "Rag-5xfAD" mice exhibit a greater than twofold increase in β-amyloid (Aβ) pathology. Gene expression analysis of the brain implicates altered innate and adaptive immune pathways, including changes in cytokine/chemokine signaling and decreased Ig-mediated processes. Neuroinflammation is also greatly exacerbated in Rag-5xfAD mice as indicated by a shift in microglial phenotype, increased cytokine production, and reduced phagocytic capacity. In contrast, immune-intact 5xfAD mice exhibit elevated levels of nonamyloid reactive IgGs in association with microglia, and treatment of Rag-5xfAD mice or microglial cells with preimmune IgG enhances Aβ clearance. Last, we performed bone marrow transplantation studies in Rag-5xfAD mice, revealing that replacement of these missing adaptive immune populations can dramatically reduce AD pathology. Taken together, these data strongly suggest that adaptive immune cell populations play an important role in restraining AD pathology. In contrast, depletion of B cells and their appropriate activation by T cells leads to a loss of adaptiveinnate immunity cross talk and accelerated disease progression.is the leading cause of age-related neurodegeneration, affecting over 5.2 million people in the United States alone (1). Pathologically, AD is characterized by two hallmark protein aggregates, amyloid-β (Aβ) plaques and neurofibrillary tangles, that are accompanied by neuroinflammation, including microgliosis, elevated cytokine production, and activation of complement pathways (2-5). Initially, microglia respond to and surround plaques, degrading Aβ by phagocytosis (for review, see refs. 6-8). However, chronic activation of these cells shift microglia to a more proinflammatory and less phagocytic state (9, 10). Although much of the data implicating microglia in AD has come from neuropathological investigation, recent genome-wide association studies have provided the first genetic evidence (to our knowledge) linking microglia dysfunction to AD, with the discovery of risk polymorphisms in several immune system genes: CR1, TREM2, CD33, HLA-DRB5, MS4A6A, and ABCA7 (8,(11)(12)(13)(14)(15).In contrast to the field's increasing understanding of the role of innate immunity in AD, comparatively little is known about whether the adaptive immune system might also influence AD. Those studies that have examined these peripheral populations have largely focused on questions about their potential as biomarkers or their role in active Aβ immunization (3, 16). However, the adaptive and innate immune systems rarely fu...

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Microglial dysfunction in brain aging and Alzheimer's disease

Cited by 492 publications

References 151 publications

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

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