TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy
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Updated: Mar 21, 2026
A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
Peng Yuan1, Carlo Condello2, C Dirk Keene3
1Department of Neurology, Yale University, New Haven, CT 06511, USA; Department of Neuroscience, Yale University, New Haven, CT 06511, USA.
Abstract:
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.
Insights
TREM2 gene variants increase Alzheimer's disease risk by impairing microglia's ability to surround amyloid plaques. This disruption leads to more exposed amyloid, causing greater neuronal damage and tau pathology, suggesting a new therapeutic target.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Haplodeficiency of the TREM2 gene in microglia is linked to increased risk for late-onset Alzheimer's disease (AD).
- The precise mechanisms by which TREM2 influences AD pathogenesis remain unclear.
- Microglia play a crucial role in brain immunity and response to neurodegenerative processes.
Purpose of the Study:
- To investigate the role of TREM2 in microglia's interaction with amyloid deposits in Alzheimer's disease.
- To elucidate how TREM2 deficiency affects the structural integrity and neurotoxic potential of amyloid plaques.
- To explore potential therapeutic strategies targeting the microglia-amyloid barrier.
Main Methods:
- High-resolution confocal and super-resolution (STORM) microscopy were employed.
- Studies were conducted using AD-like mouse models and human AD brain tissue.
- Analysis focused on the interaction between microglia processes, TREM2, and amyloid fibrils/plaques.
Main Results:
- Microglia processes, enriched with TREM2, were observed to tightly envelop early amyloid fibrils and plaques, promoting compaction and insulation.
- In TREM2- or DAP12-haplodeficient mice and in humans with R47H TREM2 mutations, microglia exhibited a significantly reduced capacity to surround amyloid deposits.
- This impairment resulted in less compact plaques with increased surface exposure of amyloid fibrils to adjacent neurites, correlating with heightened neuritic tau hyperphosphorylation and axonal dystrophy.
Conclusions:
- TREM2 deficiency disrupts the formation of a neuroprotective microglia barrier crucial for regulating amyloid plaque compaction and insulation.
- Impaired microglia barrier function due to TREM2 deficiency exacerbates amyloid-induced neurotoxicity and tau pathology.
- Targeting and modulating this microglia-amyloid barrier represents a potential novel therapeutic avenue for Alzheimer's disease.
