Alzheimer’s disease (AD) is the most common form of dementia for which there is no effective treatment. Mounting evidence suggests that the accumulation and aggregation of amyloid-β (Aβ) is a key initiating factor in a cascade of events that lead to AD (1). The AD brain is typified by a robust microglial immune response triggered by Aβ accumulation (2). Furthermore, genetic studies have linked many immune genes subserving this microglial response to the risk of AD (3, 4). Although microglia have emerged as an important player in AD pathogenesis and progression, the role of these cells in disease is complex and still not fully understood.

Increased dietary intake of niacin (nicotinic acid) has been associated with improved cognitive performance (5) and reduced risk of age-associated cognitive decline and AD (6). Niacin is obtained principally through diet and is able to cross the blood-brain barrier (7), as evidenced by its detection in the mouse brain and human cerebrospinal fluid (8, 9). Thus, we postulated that the actions of niacin within the brain may be of therapeutic utility for AD. In the brain, it is unlikely that niacin acts through its canonical role as precursor of nicotinamide adenine dinucleotide (10) because the expression and activity of the enzymatic machinery required for this conversion are markedly low (11–14). Niacin has been identified as a high-affinity ligand for the Gi-linked heterotrimeric guanine nucleotide-binding protein–coupled receptor (GPCR) hydroxycarboxylic acid receptor 2 (HCAR2), also known as GPR109A (15–17), which is expressed in the brain and has been shown to modulate microglial actions in several central nervous system (CNS) disease models (18–22). Specifically, HCAR2 activation with niacin and other ligands inhibits lipopolysaccharide–triggered inflammatory responses in microglial cells (18–20). Furthermore, niacin acts broadly through HCAR2 to elicit therapeutic effects in a demyelination model by improving microglial surveillance and increasing phagocytosis and cytokine production (21). Similarly, niacin treatment was beneficial in a glioblastoma model by increasing microglia chemotaxis and cytokine production (22). However, it is unknown whether HCAR2 modulation can affect microglial functions in AD. We hypothesized that HCAR2 promotes a beneficial microglia phenotype in AD that can be pharmacologically stimulated by niacin.

Here, we report a robust induction of HCAR2 in the brain of the amyloidogenic 5xFAD mouse model and in patients with AD. Genetic inactivation of Hcar2 in the 5xFAD mice impairs the microglial response to amyloid pathology, accompanied by an exacerbation of plaque burden, neuronal pathology, and ultimately, cognitive impairment. Conversely, persistent activation of HCAR2 with a U.S. Food and Drug Administration (FDA)–approved formulation of niacin, Niaspan, stimulates a broad and complex protective response mediated by microglia, leading to decreased plaque burden, reduced neuronal loss, and improved working memory deficits. Our findings support HCAR2 activation as a promising therapeutic strategy for AD.