Microglial HCAR2 as a therapeutic target for tau pathology in alzheimer's disease

Overview

This research program targets the microglial niacin receptor HCAR2 (GPR109A) as a promising therapeutic strategy for Alzheimer's disease (AD), with a specific focus on tau pathology present at symptomatic stages. Microglia, the resident immune cells of the brain, play complex roles in neurodegeneration, and identifying selective microglial targets is critical for developing effective AD treatments. The team has identified HCAR2 as selectively expressed by microglia and demonstrated that it promotes a neuroprotective microglial phenotype. Preliminary data show that HCAR2 inactivation exacerbates both amyloid burden and hyperphosphorylated tau accumulation in preclinical mouse models, suggesting that pharmacological stimulation of HCAR2 could enhance microglial clearance of pathological tau. An FDA-approved nicotinic acid (niacin) formulation has already been shown to stimulate this protective phenotype, offering a potential accelerated path to therapeutic development.

Technical specifications

Key research findings and capabilities:

• HCAR2 is selectively expressed by microglia in the brain and is dramatically induced in AD
• Constitutive HCAR2 inactivation in 5xFAD mice leads to exacerbated amyloid burden and neuronal loss at 4–6 months
• HCAR2-deficient 5xFAD mice show dramatically increased hyperphosphorylated tau in cortex and subiculum, with p-tau accumulation within microglia engaging amyloid plaques
• Pharmacological stimulation of HCAR2 using an FDA-approved niacin formulation promotes protective microglial phenotypes in preclinical AD models
• Conditional microglial-specific HCAR2 knockout line currently being expanded for use in the PS19 tauopathy model
• Planned analyses include hyperphosphorylated tau levels, tau seeding potential, microglia phenotyping, brain atrophy assessment, and behavioral testing
• Primary microglia cultures (wild-type and HCAR2 knockout) will be used to examine tau uptake, clearance, and tau seed release
• Single-cell transcriptomics and MRI capabilities to support mechanistic and structural analyses

Technology readiness level

This research is at an early-to-mid preclinical stage. HCAR2 has been validated as a relevant microglial target through genetic loss-of-function studies in the 5xFAD amyloid model, and preliminary data suggest a role in tau clearance. A conditional knockout line for microglial-specific HCAR2 inactivation is currently being expanded, and validation in the PS19 tauopathy model is planned over a two-year study period. The use of an FDA-approved niacin formulation as a pharmacological tool provides a translational foundation, though identification and characterization of potent, selective HCAR2 agonists suitable for a drug development pipeline remains a future goal. The program is seeking partnership support for animal model expansion, single-cell transcriptomics, MRI, and key personnel to advance toward therapeutic candidate development.