Activation of the niacin receptor HCAR2 to mitigate tau pathology

Indiana University Indianapolis, Indianapolis IN

Investigators

Abstract

Abstract Tauopathies are a group of devastating neurodegenerative diseases, such as frontotemporal lobar degeneration (FTLD)-tau or Alzheimer’s disease (AD), that are characterized by the presence of pathological hyperphosphorylated and misfolded aggregates of the microtubule-associated protein tau. There are no effective treatments for tauopathies. Interestingly, it has been reported that higher intake of niacin (also known as nicotinic acid) correlates with reduced risk of AD, which suggests that niacin may protect against pathogenic tau-induced neurodegeneration and could be of therapeutic utility. Niacin can cross the blood brain barrier and directly activate HCAR2 (GPR109A), a GPCR that is expressed in the brain selectively by microglia. HCAR2 activation by niacin and other ligands have been demonstrated to elicit a protective microglial response and overall salutary effects in different models of neuronal injury or neurodegeneration. However, an HCAR2-directed therapeutic strategy has not been tested for tauopathies. We hypothesize that HCAR2 activation with niacin may be a promising therapeutic strategy for tau pathology. Importantly, there are FDA-approved formulations of niacin, which could potentially be rapidly repurposed for tauopathies in the clinical context. We provide preliminary evidence that pathological tau induces HCAR2 expression by microglia. Inactivation of Hcar2 in tauopathy mouse models leads to exacerbation of the disease, suggesting a protective effect of HCAR2. Conversely, treatment with niacin reduced neuronal loss, motor deficits, tau phosphorylation, propagation and seeding activity in these models. Aim 1) Study the therapeutic potential of HCAR2 in tauopathy preclinical models We aim to establish an effective therapeutic strategy for the treatment of tau pathology by activating HCAR2. The HCAR2 agonist niacin will be delivered to pre-clinical tauopathy mouse models by enriched diet or oral gavage using the FDA- approved formulation Niacin-ER. Furthermore, HCAR2 will be selectively inactivated in microglia cells in tauopathy mouse models after disease onset. The effects of niacin treatment and Hcar2 deletion on tau pathology will be assessed in PS19 mice and the effects on tau spreading will be analyzed in mice injected with an AAV encoding pathogenic tau. Aim 2) Determine the cellular mechanism subserving HCAR2 actions on tau pathology. We propose to establish the cellular mechanisms and pathways underlying the role of HCAR2 on tau clearance using a combination of pharmacological, genetic, and omics approaches. We postulate activation of HCAR2 induces the clearance of pathogenic tau species by microglia, overall reducing the propagation of tau pathology. Microglia cultures will be used to assess the role of HCAR2 on tau uptake, intracellular degradation, and release of pathogenic forms of tau. Elucidating the mechanisms subserving HCAR2 actions will allow us to understand how this therapeutic strategy can be further improved and identify novel potential pharmacological targets.