Inflammation in Alzheimer Disease--A Brief Review of the Basic Science and Clinical Literature

Wyss‐Coray, Tony; Rogers, Joseph

doi:10.1101/cshperspect.a006346

Cited by 844 publications

(680 citation statements)

References 248 publications

(249 reference statements)

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“…6 The causative role of Aβ is particularly compelling given the location and morphology of amyloid plaques in cases of amyloid angiopathy. However, other mechanisms not specific to aberrant Aβ have also been implicated in vascular pathology in AD such as inflammation, 19 thrombin, 20 and cholinergic dysfunction 21 all of which may coexist with tau pathology and/or neurodegeneration. While the data presented in this study does not directly discount the importance of these contributions, it does suggest that tau itself is not a driver of impaired CVR and supports the hypothesis of a fundamental role of amyloid pathology in the vascular abnormalities observed in AD.…”

Section: Discussionmentioning

confidence: 99%

Increased Cerebral Vascular Reactivity in the Tau Expressing rTg4510 Mouse: Evidence against the Role of Tau Pathology to Impair Vascular Health in Alzheimer's Disease

Wells

Holmes

O’Callaghan

et al. 2015

J Cereb Blood Flow Metab

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Vascular abnormalities are a key feature of Alzheimer's disease (AD). Imaging of cerebral vascular reactivity (CVR) is a powerful tool to investigate vascular health in clinical populations although the cause of reduced CVR in AD patients is not fully understood. We investigated the specific role of tau pathology in CVR derangement in AD using the rTg4510 mouse model. We observed an increase in CVR in cortical regions with tau pathology. These data suggest that tau pathology alone does not produce the clinically observed decreases in CVR and implicates amyloid pathology as the dominant etiology of impaired CVR in AD patients.

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Section: Discussionmentioning

confidence: 99%

Increased Cerebral Vascular Reactivity in the Tau Expressing rTg4510 Mouse: Evidence against the Role of Tau Pathology to Impair Vascular Health in Alzheimer's Disease

Wells

Holmes

O’Callaghan

et al. 2015

J Cereb Blood Flow Metab

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“…Microglia surround amyloid plaques in human AD brains. Their role in AD pathogenesis is complex and includes engulfing or degrading amyloid plaques and promoting neurotoxicity through excessive inflammatory cytokine release (Wyss‐Coray & Rogers, 2012). However, it remains unclear whether microglia phagocytose Aβ fibrils in vivo (Prokop, Miller, & Heppner, 2013).…”

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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“…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)(3)(4)(5). Initially, microglia respond to and surround plaques, degrading Aβ by phagocytosis (for review, see refs.…”

mentioning

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.

344

287

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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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Inflammation in Alzheimer Disease--A Brief Review of the Basic Science and Clinical Literature

Cited by 844 publications

References 248 publications

Increased Cerebral Vascular Reactivity in the Tau Expressing rTg4510 Mouse: Evidence against the Role of Tau Pathology to Impair Vascular Health in Alzheimer's Disease

Increased Cerebral Vascular Reactivity in the Tau Expressing rTg4510 Mouse: Evidence against the Role of Tau Pathology to Impair Vascular Health in Alzheimer's Disease

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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