TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy

Abstract

Summary Haplodeficiency of the microglia gene TREM2 increases risk for late-onset Alzheimer’s disease (AD) but the mechanisms remain uncertain. To investigate this, we used high-resolution confocal and super-resolution (STORM) microscopy in AD-like mice and human AD tissue. We found that microglia processes, rich in TREM2, tightly surround early amyloid fibrils and plaques promoting their compaction and insulation. In Trem2 or DAP12 haplodeficient mice and in humans with R47H TREM2 mutations, microglia had a markedly reduced ability to envelop amyloid deposits. This led to an increase in less compact plaques with longer and branched amyloid fibrils resulting in greater surface exposure to adjacent neurites. This was associated with more severe neuritic tau hyperphosphorylation and axonal dystrophy around amyloid deposits. Thus, TREM2 deficiency may disrupt the formation of a neuroprotective microglia barrier that regulates amyloid compaction and insulation. Pharmacological modulation of this barrier could be a novel therapeutic strategy for AD.

Alzheimer's disease pathology in Nasu-Hakola disease brains

“…Loss of TREM2 function reduces the ability of microglia to engulf Aβ (15). AD patients with the TREM2 variant of R47H showed fewer microglia surrounding plaques, increased numbers of filamentous non-compacted plaques, and more p-tau-positive neurites around plaques (10). In all NHD cases, we found several small Aβ-immunoreactive deposits, and some of them might represent axonal spheroids located chiefly in the white matter of the frontal cortex and the hippocampus (Figure 1a-c).…”

“…TREM2 deficiency induces apoptosis of microglia and reduces recruitment of microglia around Aβ plaques in the brains of mouse models of AD (4). Furthermore, microglial processes enriched in TREM2 tightly surround early amyloid fibrils and plaques, and promote their compaction and insulation (10). 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).…”

“…Furthermore, microglial processes enriched in TREM2 tightly surround early amyloid fibrils and plaques, and promote their compaction and insulation (10). 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).…”

“…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.…”