Targeting microglia with niacin
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.
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.
Furthermore, according to the human equivalent doses based on body surface area (64), the dosage of Niaspan used to treat mice corresponds to a daily dosage of about 500 mg of Niaspan in humans, which is well below the daily maintenance dose used to treat dyslipidemia (1000 to 2000 mg). Thus, our findings suggest that a low and safe dose of Niaspan might be sufficient to elicit therapeutic effects in AD and are consistent with the existing epidemiological data showing that enhanced dietary niacin is associated with reduced risk for AD.