The role of microglia niacin receptor (HCAR2) in Alzheimer's disease.

Abstract

Dietary intake of niacin reduces the risk of Alzheimer´s disease (AD) and protects against age-related cognitive decline. Niacin is a ligand for the niacin receptor (HCAR2), which, in the brain, is selectively expressed by microglia. HCAR2 is significantly increased in the AD brain, and activation of this receptor has been shown to be neuroprotective in stroke and demyelination models. Thus, we hypothesized that microglial HCAR2 plays a protective role in AD. To understand the role of HCAR2 in AD, we compared disease progression of the AD mouse model 5xFAD lacking the Hcar2 gene (5xFAD;Hcar2 -/- ) with 5xFAD;Hcar2 +/+ . Plaque burden, neuronal loss, microglial function, cognition and gene expression were analyzed in both genotypes at 4 and 6 months of age. Furthermore, 5 month-old 5xFAD mice were treated with a FDA-approved formulation of niacin (Niaspan®) daily, by oral gavage for 30 days with 100 mg niacin/kg to assess the effects of pharmacological activation of HCAR2 on disease progression in these mice. Our results show a dramatic increase of microglial HCAR2 expression in the AD brain. In 5xFAD mice, the induction of Hcar2 is selective for microglia associated with amyloid plaques. 5xFAD;Hcar2 -/- exhibit a more severe amyloid pathology compared to controls, increased plaque load and neuronal loss, decreased Aβ phagocytosis by microglia and accelerated onset of cognitive deficits. On the other hand, activation of HCAR2 in 5xFAD with niacin treatment reduces neuronal loss and plaque burden, increases Aβ phagocytosis and rescues working memory deficits. Our data suggest the microglia receptor HCAR2 plays a protective role in AD, and is part of an endogenous response from microglia to tackle the disease. HCAR2 is a potential therapeutic target to modulate microglia phenotype towards beneficial outcomes in AD. Our results indicate that the activation of HCAR2 with the FDA-approved formulation of niacin, Niaspan®, leads to neuroprotective effects in AD, even after the onset of severe amyloid pathology, highlighting the translational potential of this strategy into clinical practice, supporting further study of this therapeutic approach.