The niacin receptor HCAR2 modulates microglial response and limits disease progression in a mouse model of Alzheimer's disease

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-beta (A beta), 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.

Automated summary

Increased dietary intake of niacin is associated with a reduced risk of Alzheimer's disease (AD). Niacin acts as a ligand for the receptor HCAR2 (GPR109A), which is selectively expressed by microglia in the brain and is induced by amyloid pathology in AD. Genetic inactivation of Hcar2 in AD mouse models impairs the microglial response to amyloid deposition, while activation of HCAR2 with an FDA-approved formulation of niacin leads to reduced plaque burden and neuronal dystrophy, as well as improved working memory deficits.