Activated microglia mitigate Aβ-associated tau seeding and spreading.

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Alzheimer's disease (AD) involves amyloid-beta (Aβ) plaques and tau pathology.
• TREM2 gene variants are associated with AD risk, affecting microglial responses.
• The role of TREM2 in microglial function regarding tau pathology is not fully understood.

Purpose of the Study:

• To investigate the role of TREM2 and microglial function in the seeding and spreading of tau pathology in Alzheimer's disease models.
• To determine if microglial depletion and repopulation affect Aβ-driven tau propagation.

Main Methods:

• Utilized TREM2 knockout (TREM2KO) mouse models and microglial ablation/repopulation strategies.
• Assessed tau seeding and spreading in the presence and absence of microglia and TREM2.
• Analyzed disease-associated microglia (DAM) gene expression.

Main Results:

• Both TREM2 deficiency and microglial ablation significantly enhanced tau seeding and spreading around Aβ plaques.
• Microglial repopulation around plaques did not restore protective functions; instead, it showed reduced DAM gene expression and increased tau pathology.
• TREM2-dependent activation of the DAM phenotype is critical for mitigating Aβ-induced tau propagation.

Conclusions:

• TREM2-dependent microglial activation, specifically the DAM phenotype, is essential for delaying the pathological spread of tau aggregates in Alzheimer's disease.
• Loss of TREM2 function or microglial dysfunction exacerbates tau seeding and spreading, highlighting the protective role of activated microglia.