Volume 16, Issue S9 e040679
DRUG DEVELOPMENT
Free Access

Therapeutic potential of niacin in Alzheimer's disease

Nonhuman/Target identification and validation studies: Other

Miguel Moutinho,

Corresponding Author

Miguel Moutinho

Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA

Correspondence

Miguel Moutinho, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.

Email: mmoutinh@iu.edu

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Andy P. Tsai,

Andy P. Tsai

Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA

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Shweta S Puntambekar,

Shweta S Puntambekar

Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA

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Jheel Patel,

Jheel Patel

Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA

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Peter B. Lin,

Peter B. Lin

Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA

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Vaishnavi Jadhav,

Vaishnavi Jadhav

Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA

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Roxanne Y Williams,

Roxanne Y Williams

Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA

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Anantha Shekhar,

Anantha Shekhar

Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA

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Gary E. Landreth,

Gary E. Landreth

Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA

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First published: 07 December 2020

Abstract

Background

Dietary intake of niacin reduces the risk of Alzheimer's disease (AD) and protects against age-related cognitive decline. Niacin is a ligand for the niacin receptor HCAR2, which, in the brain, is selectively expressed by microglia. HCAR2 activation has been shown to be neuroprotective in stroke and demyelination models. Therefore, we hypothesized that niacin administration could have beneficial effects in AD pathology.

Method

5 month-old 5xFAD mice, an animal model of AD, were treated with a FDA-approved formulation of niacin (Niaspan®) daily, by oral gavage for 30 days with 100 mg niacin/kg. After treatment, the animals were sacrificed and the brains were collected for immunohistochemistry and biochemical analysis. Gene expression and Aβ uptake efficiency were analyzed in primary cultures of microglia incubated with 1.25 nM of Niaspan®.

Result

Our results indicate there is an induction of HCAR2 expression in the AD brain, prominently in activated microglia. Niaspan® treatment significantly reduced Aβ burden and number of compact plaques in 5xFAD brain. Accordingly, Niaspan® induced phagocytic genes and Aβ uptake in primary cultures of microglia. Importantly, Niaspan® exerted a neuroprotective effect evidenced by reduced neuronal loss in the subiculum and cortical layer 5 of Niaspan®-treated mice, accompanied by a rescue of working memory deficits.

Conclusion

These preliminary data suggest that Niaspan® treatment has neuroprotective effects in AD, even after the onset of severe amyloid pathology, through an induction of Aβ cleareance by microglia. Niaspan® is a FDA-approved drug, thus there is a translational potential of this strategy into clinical practice, supporting further study of this therapeutic approach.