Parenchymal border macrophages regulate tau pathology and tau-mediated neurodegeneration

Area of Science:

• Neuroscience
• Immunology
• Neurodegenerative Diseases

Background:

• Parenchymal border macrophages (PBMs) are crucial for central nervous system (CNS) homeostasis and cerebrospinal fluid (CSF) flow.
• PBMs facilitate amyloid-beta clearance, a key factor in Alzheimer's disease (AD).
• The role of PBMs in tauopathies, another neurodegenerative condition, remains largely unexplored.

Purpose of the Study:

• To investigate the impact of tau pathology on CSF flow and PBM populations.
• To determine if PBM dysfunction exacerbates tau pathology and neurodegeneration.
• To identify PBMs as potential therapeutic targets in tauopathies.

Main Methods:

• Utilized the PS19 mouse model exhibiting tau pathology.
• Assessed CSF flow dynamics and PBM subpopulations (including MHCII+ PBMs).
• Pharmacologically depleted PBMs in PS19 mice to evaluate effects on tau pathology and neurodegeneration.

Main Results:

• PS19 mice showed reduced CSF flow and an increased MHCII+ PBM subpopulation compared to wild-type littermates.
• Pharmacological depletion of PBMs in PS19 mice significantly increased tau pathology and tau-dependent neurodegeneration.
• The exacerbation of neurodegeneration was independent of gliosis or aquaporin-4 depolarization.

Conclusions:

• Parenchymal border macrophages are novel cellular regulators of tau pathology.
• PBMs play a critical role in modulating tau-mediated neurodegeneration.
• Targeting PBMs may offer a new therapeutic strategy for tauopathies.