Repurposing FDA-approved agonists of HCAR2 as novel therapeutics for Alzheimer's Disease

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Alzheimer’s disease (AD) is a devastating neurodegenerative disease for which there are no effective treatments. Low dietary niacin intake increases the risk of cognitive frailty and niacin deficiency leads to neurodegeneration. Conversely, higher niacin intake is associated with improved cognitive performance, reduced risk of cognitive decline and AD. Niacin actions in the brain are distinct from other tissues where it is not used as a metabolic substrate, but exerts its actions principally through its ability to activate HCAR2 (GPR109A), a GPCR that is expressed in the brain selectively by microglia. Niaspan® is the FDA approved formulation of niacin and is used clinically to treat dyslipidemia. Recenty, it has been appreciated that monomethyl fumarate (MMF), the bioactive metabolite of dimethyl fumarate (DMF) is an agonist of HCAR2. Tecfidera® is the FDA-approved formulation of DMF used clinically to treat multiple sclerosis (MS). HCAR2 activation with niacin or DMF elicits neuroprotective effects in Parkinson's disease, stroke, and MS models. Niacin treatment of Parkinson’s patients improved clinical outcomes and there is an ongoing clinical trial (NCT03808961). Niacin treatment of a murine model of MS, induces a protective microglial phenotype. The effect of these agonists has not been investigated in AD or its animal models. We hypothesize that agonists of HCAR2 are of therapeutic utility in AD. We provide preliminary evidence there is a robust induction of HCAR2 expression by microglia in the AD brain. Genetic inactivation of Hcar2 increases plaque burden and accelerates cognitive impairment in 5xFAD AD mouse model. Conversely, Niaspan® treatment reduced plaque burden and neuronal pathology, suggesting that pharmacological activation of HCAR2 is a viable therapeutic strategy for AD. We will study the repuporsing potential of the FDA-approved agonists of HCAR2, Niaspan® and Tecfidera® for AD in the preclinical level using the 5xFAD mouse model of AD. Aim 1) Evaluate the therapeutic efficacy and pharmacological target of the FDA-approved drugs Niaspan® and Tecfidera® in the 5xFAD amyloidogenic mouse model We propose to establish an optimal effective therapeutic strategy for treatment of 5xFAD mice. We will treat mice with HCAR2 agonists at early and late disease stages and for diferent periods of time. Drug efficacy will be evaluated by a battery of phenotypic and behavioral readouts. Pharmacokinetic and pharmacodynamic studies will be performed. We will establish whether the effects HCAR2 agonists arise exclusively from microglial HCAR2 by its selective and inducible inactivation using Cx3cr1CreERT2;Hcar2fl/fl;5xFAD mice. Aim 2) Analyze microglial transcriptomic profiles induced by Niaspan® and Tecfidera® in AD We will determine the effect of Niaspan® and Tecfidera® on the microglial transcriptome by RNA-seq analysis of cultured microglia activated with Aβ1-42 aggregates and treated with these drugs. Both primary murine microglia and human pluripotent stem cells (hPSC)-derived microglia will be analyzed to establish if the actions of Niaspan® and Tecfidera® are comparable between human and murine microglia. We will carry out a parallel in vivo analysis of microglial subpopulations expressing high and low levels of Hcar2 isolated from 5xFAD mice treated with Niaspan® and Tecfidera® using an mRFP-reporter line. These studies will identify target genes and pathways modulated by HCAR2 activation in microglia which subserve its neuroprotective effects in AD, and allow the dissection of underlying mechanisms.