| Autor: |
Moutinho M; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.; Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Puntambekar SS; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Tsai AP; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Coronel I; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.; Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Lin PB; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Casali BT; Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA., Martinez P; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.; Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Oblak AL; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.; Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Lasagna-Reeves CA; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.; Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Lamb BT; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Landreth GE; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.; Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. |
| Abstrakt: |
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. |
