Microglia have been shown to contribute in Alzheimer’s disease (AD) pathophysiology. However, the role of these cells remains to be completely elucidated. Here, Moutinho et al. investigated the mechanisms mediating the association between dietary intake of nicotinic acid (niacin) and the reduced risk of developing AD. The expression of niacin receptor HCAR2 is increased in brain from patients with AD and in rodent models. Hcar2 inactivation in AD mice exacerbated cognitive impairments and amyloid-β burden, whereas HCAR2 activation using the FDA-approved drug Niaspan had protective and therapeutic effects in mice by modulating the microglia response to amyloid pathology. The results suggest that modulating microglia activity through HCAR2 might be effective for preventing or treating AD.

Increased dietary intake of niacin has been correlated with reduced risk of Alzheimer’s disease (AD). Niacin serves as a high-affinity ligand for the receptor HCAR2 (GPR109A). In the brain, HCAR2 is expressed selectively by microglia and is robustly induced by amyloid pathology in AD. The genetic inactivation of Hcar2 in 5xFAD mice, a model of AD, results in impairment of the microglial response to amyloid deposition, including deficits in gene expression, proliferation, envelopment of amyloid plaques, and uptake of amyloid-β (Aβ), ultimately leading to exacerbation of amyloid burden, neuronal loss, and cognitive deficits. In contrast, activation of HCAR2 with an FDA-approved formulation of niacin (Niaspan) in 5xFAD mice leads to reduced plaque burden and neuronal dystrophy, attenuation of neuronal loss, and rescue of working memory deficits. These data provide direct evidence that HCAR2 is required for an efficient and neuroprotective response of microglia to amyloid pathology. Administration of Niaspan potentiates the HCAR2-mediated microglial protective response and consequently attenuates amyloid-induced pathology, suggesting that its use may be a promising therapeutic approach to AD that specifically targets the neuroimmune response.