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

Abstract

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...

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

“…Aducanumab, derived from a naturally occurring human autoantibody against Cu 2+ -modified Aβ aggregates (which are the most neuro toxic Aβ species in the AD brain), showed promise in clearing brain Aβ deposits and improving cognition in a 2016 phase Ib trial 57 . Lymphocytes (including B cells, T cells and natural killer cells) also participate in Aβ clearance via immunoglobulin-mediated adaptive phagocytosis 58,59 . Future studies will help to elucidate the crosstalk between innate immunity and adaptive 169,170 .…”

Can Better Management of Periodontal Disease Delay the Onset and Progression of Alzheimer’s Disease?

“…Systemic hypoxia from co-morbid vascular states (atherosclerosis/stroke) [72,73] and paucity of peripheral adaptive immune cells in the AD brain, and from Rag-5xfAD mice, demonstrates enhanced neuroinflammation and Aβ accumulation compared to control animals [36]. This research helps to explain Aβ deposition and abnormal tau phosphorylation post stroke.…”

“…Already disturbed adaptive immune responses, as is apparent from the host suffering from periodontal disease [34], will give rise to oral pathology. Marsh et al [36] have verified the role of adaptive immune cells in the immune-deficient transgenic AD mouse model (Rag5xfAD). This report confirms that adaptive immune cells in an immune-sufficient host (control animals) help to restrain both neuroinflammation and accumulation of Aβ protein [36], suggesting organ specific hallmark pathology can develop in the immunosuppressed vulnerable host.…”

Central Nervous System: (Immunological) Ivory Tower or Not?

“…A large body of literature has documented the finding that mice lacking an adaptive immune system (T and B lymphocytes) show impaired cognitive function and aberrant stress responses (Bartholomaus et al, 2009;Brynskikh et al, 2008;Derecki et al, 2010;Kipnis et al, 2004;Marques et al, 2009;Marsh et al, 2016;Ziv et al, 2006;Filiano et al, 2016). Such mice demonstrate spatial memory deficits and decreased adult neurogenesis (Derecki et al, 2010;Wolf et al, 2009;Ziv et al, 2006).…”

“…Such mice demonstrate spatial memory deficits and decreased adult neurogenesis (Derecki et al, 2010;Wolf et al, 2009;Ziv et al, 2006). Reconstitution of immunodeficient mice with a full complement of lymphocytes (through either bone marrow or adoptive transfer) restores their learning ability as well as their neurogenic capacity (Brynskikh et al, 2008;Derecki et al, 2010;Marsh et al, 2016). Interestingly, repopulation with CD4+ T cells alone (but not with CD8+ or B cells) is sufficient to rescue their phenotypes, indicating that helper T cells play an important role in supporting CNS functions (Wolf et al, 2009).…”