TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques

Abstract

Wang et al. report that TREM2 protects mice from Alzheimer's disease by enabling resident microglia to insulate and alter Aβ plaque structure, thereby limiting neuritic damage.

TREM2, Microglia, and Neurodegenerative Diseases

“…To determine whether peripheral macrophages contribute to the brain myeloid population in b-amyloidosis models, one study [140] used parabiosis to combine the circulatory systems of mice from either the [ 5 3 0 _ T D $ D I F F ] 5ÂFAD model or from the APPPS1-21 model (each expressing the CD45.2 allele) to age-matched mice expressing CD45.1. After 4 weeks [ 5 4 1 _ T D $ D I F F ] (5ÂFAD) or 9 weeks (APPPS1-21) of conjoined circulation, myeloid cells in the spleens and lungs showed substantial contributions from both parabionts [140].…”

“…After 4 weeks [ 5 4 1 _ T D $ D I F F ] (5ÂFAD) or 9 weeks (APPPS1-21) of conjoined circulation, myeloid cells in the spleens and lungs showed substantial contributions from both parabionts [140]. In the brains, however, essentially all myeloid cells displayed only the CD45 reactivity of the host animal, providing strong evidence that the proportion of plaque-associated myeloid cells derived from infiltrating macrophages was negligible.…”

“…Because TREM2 is implicated in phagocytosis and in restraining proinflammatory TLR signaling, one expectation would be that AD mice lacking TREM2 should display exacerbated amyloid plaque burden and inflammation with heightened cytokine production. Instead, different groups have reported inconsistent findings regarding plaque pathology and dampened rather than aggravated microglial activation [54,[138][139][140].…”

Alzheimer's disease pathology in Nasu-Hakola disease brains

“…In TREM2-or DAP12-deficient mouse models of AD, microglia showed a markedly reduced ability to envelope amyloid deposits, leading to an increase in less compact and more diffuse plaques associated with greater neuritic damage (10). These observations suggest that TREM2/ DAP12-mediated microglial response limits diffusion and toxicity of amyloid plaques by forming a protective barrier (10,11). However, at present, the levels of Aβ deposition in postmortem NHD brains, where the biological function of TREM2/DAP12 signaling pathway is completely lost, remain unknown.…”

Neurodegeneration: From cellular concepts to clinical applications

“…the brain microglial cells, are also associated with a 2 to 4-fold increase in AD risk (15). Research investigating the biology of TREM2 points to a possible role for this receptor in modulating the brain's response to protein aggregation by enabling microglial cells to contain neuritic damage (16)(17)(18). APOE and TREM2 may thus represent a link between Aβ aggregation, toxicity, and the clinical presentation of AD.…”