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Published on: September 3, 2021
Chronic TREM2 activation exacerbates Aβ-associated tau seeding and spreading
Nimansha Jain1,2,3, Caroline A Lewis1,2,3, Jason D Ulrich1,2,3
1Department of Neurology, Washington University School of Medicine, St. Louis, MO.
Abstract:
Variants in the triggering receptor expressed on myeloid cells 2 (TREM2) gene are associated with increased risk for late-onset AD. Genetic loss of or decreased TREM2 function impairs the microglial response to amyloid-β (Aβ) plaques, resulting in more diffuse Aβ plaques and increased peri-plaque neuritic dystrophy and AD-tau seeding. Thus, microglia and TREM2 are at a critical intersection of Aβ and tau pathologies in AD. Since genetically decreasing TREM2 function increases Aβ-induced tau seeding, we hypothesized that chronically increasing TREM2 signaling would decrease amyloid-induced tau-seeding and spreading. Using a mouse model of amyloidosis in which AD-tau is injected into the brain to induce Aβ-dependent tau seeding/spreading, we found that chronic administration of an activating TREM2 antibody increases peri-plaque microglial activation but surprisingly increases peri-plaque NP-tau pathology and neuritic dystrophy, without altering Aβ plaque burden. Our data suggest that sustained microglial activation through TREM2 that does not result in strong amyloid removal may exacerbate Aβ-induced tau pathology, which may have important clinical implications.
Insights
Activating TREM2 signaling in Alzheimer's disease models surprisingly worsened tau pathology. Sustained microglial activation without amyloid clearance may increase neuroinflammation and disease progression.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Triggering receptor expressed on myeloid cells 2 (TREM2) variants increase late-onset Alzheimer's disease (AD) risk.
- TREM2 dysfunction impairs microglial response to amyloid-β (Aβ) plaques, leading to diffuse plaques and increased tau pathology.
Purpose of the Study:
- To investigate if chronic TREM2 signaling activation can reduce Aβ-induced tau seeding and spreading.
- To understand the role of TREM2 in the interplay between Aβ and tau pathologies in AD.
Main Methods:
- Utilized a mouse model of amyloidosis with AD-tau injection to induce Aβ-dependent tau seeding.
- Administered a TREM2-activating antibody chronically to assess its effects on microglial activation, Aβ plaques, and tau pathology.
Main Results:
- Chronic TREM2 activation increased peri-plaque microglial activation.
- Surprisingly, TREM2 activation exacerbated peri-plaque tau pathology and neuritic dystrophy.
- Aβ plaque burden remained unchanged despite increased microglial activation.
Conclusions:
- Sustained TREM2-mediated microglial activation, without effective amyloid clearance, may worsen Aβ-induced tau pathology.
- These findings have significant implications for therapeutic strategies targeting TREM2 in Alzheimer's disease.
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