Impact of TREM2 risk variants on brain region-specific immune activation and plaque microenvironment in Alzheimer's disease patient brain samples

Area of Science:

• Neuroimmunology
• Alzheimer's Disease Pathogenesis
• Genetics of Neurodegeneration

Background:

• Multiple immune-related genetic risk factors implicate the immune system in sporadic Alzheimer's Disease (sAD).
• Microglia activation in human AD brains correlates with neuropathological progression, requiring both beta-Amyloid (Aβ) and tau pathology.
• TREM2 (Triggering receptor expressed on myeloid cells 2) risk variants influence AD pathology and microglia behavior.

Purpose of the Study:

• To investigate the role of immune system dysregulation in Alzheimer's Disease.
• To analyze the impact of AD-associated genetic risk variants, specifically in TREM2, on microglial response and neuropathology.
• To explore brain region-specific immune activation patterns in human AD.

Main Methods:

• Comprehensive analysis of microglia in human AD brains across different disease stages.
• Digital spatial profiling of the plaque microenvironment.
• Targeted gene expression profiling using the NanoString nCounter system.

Main Results:

• Microglia activation follows AD neuropathological progression, contingent on Aβ and tau co-occurrence.
• TREM2 risk variant carriers exhibit reduced plaque-associated microglia but increased dystrophic neurites and pathological tau.
• Significant brain region-dependent differences in immune response patterns were observed within individual cases.

Conclusions:

• Immune activation in human AD brains is complex, showing profound brain region and risk-variant specific differences.
• These findings suggest that the heterogeneity of immune responses impacts the efficacy of immune-therapeutic strategies for sAD.
• Understanding these specific immune profiles is crucial for developing targeted treatments for Alzheimer's Disease and related neurodegenerative disorders.