The niacin receptor HCAR2 induces a protective response of microglia to amyloid pathology.

Abstract Background Dietary intake of niacin correlates with reduced risk of Alzheimer´s disease (AD). Niacin is a ligand for the niacin receptor HCAR2, which, in the brain, is expressed by microglia. HCAR2 ligands have been shown to modulate microglia functions and exert neuroprotective effects in different models of neuronal injury. Therefore, we hypothesized that HCAR2 modulates a protective microglial phenotype in AD, which can be stimulated by HCAR2 agonists. Method To assess the role of HCAR2 in amyloid pathology, the brains of the AD animal model 5xFAD and 5xFAD mice lacking Hcar2 gene (5xFAD‐KO) were subjected to transcriptomic, immunohistochemistry and biochemical analysis. Furthermore, to activate HCAR2, 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. Treated animals were sacrificed and the brains were collected for immunohistochemistry and biochemical analysis. To validate that Niaspan® effects were dependent on HCAR2, we performed the same treatment paradigm and analysis using 5xFAD‐KO mice. Result Our results indicate that microglia significantly induce HCAR2 expression in the AD brain. Lack of Hcar2 in the 5xFAD mice leads to a deficient response of microglia to amyloid pathology, which is accompanied by an increase in plaque load and exacerbation of the amyloid‐associated neuropathology. Niaspan® treatment increased the response of microglia to amyloid pathology, decreased plaque burden in 5xFAD, and exerted a neuroprotective effect evidenced by reduced neuronal loss in the subiculum, accompanied by a rescue of working memory deficits. Niaspan® did not induce these beneficial effects in 5xFAD‐KO mice. Conclusion These data suggest that HCAR2 induces a protective microglial phenotype in AD. Furthermore, activation of HCAR2 by Niaspan® treatment has neuroprotective effects in AD, even after the onset of severe amyloid pathology, possibly through the stimulation of a protective microglia response. Niaspan® is a FDA‐approved drug, thus there is a translational potential of this strategy into clinical practice, supporting further study of this therapeutic approach.