Chronic TREM2 activation exacerbates Aβ-associated tau seeding and spreading

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.