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Cited by 92Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

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

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Moutinho, Miguel, Puntambekar, Shweta S., Tsai, Andy P., Coronel, Israel, Lin, Peter B., Casali, Brad T., Martinez, Pablo, Oblak, Adrian L. +3 more·2022·Science Translational Medicine
DOI 10.1126/scitranslmed.abl7634PMC PMC10161396
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Abstract

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.

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Authors
Moutinho, M., Puntambekar, S. S., Tsai, A. P., Coronel, I., Lin, P. B., Casali, B. T., Martinez, P., Oblak, A. L., Lasagna-Reeves, C. A., Lamb, B. T., & Landreth, G. E.
Affiliations
  • Indiana University Indianapolis (US)
  • Case Western Reserve University (US)
  • Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Corresponding author
Landreth, Gary E.
ORCID
Venue
Science Translational Medicine
Publisher
American Association for the Advancement of Science (AAAS)
Published
2022-03-23
Volume
14
Issue
637
Pages
eabl7634-eabl7634
ISSN
  • 1946-6234 (ISSN-L)
  • 1946-6242
DOI
10.1126/scitranslmed.abl7634
PMC
PMC10161396
OpenAlex
W4220807055
Cited by
92
References
27
Citations by year
2026: 23 · 2025: 17 · 2024: 21 · 2023: 25 · 2022: 6
FWCI
5.98
Type
journal article
Language
en
Open access
Locations
  • Science Translational Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion)
Funders
  • Alzheimer's Association
  • Eli Lilly and Company
  • Indiana Clinical and Translational Sciences Institute (P30CA082709)
  • Texas Tech University
  • Johns Hopkins University
  • Universität zu Lübeck
  • Partenariat Canadien Contre Le Cancer
  • National Institutes of Health (CA082709)
  • School of Medicine, Indiana University
  • National Institute on Aging (RF1AG051495, AG051495, P50AG005146, RF1AG076610, R01AG076610)
  • National Cancer Institute (P30CA082709)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
HCAR2, GPR109A, nicotinic acid, Alzheimer's disease, microglia, amyloid-beta, amyloid plaques, 5xFAD mice, Niaspan, neuroinflammation, neuroprotection, working memory deficits, neuronal loss, neuroimmune response
MeSH terms
Alzheimer Disease, Animals, Disease Models, Animal, Mice, Transgenic, Niacin, Amyloid beta-Peptides, Microglia, Disease Progression, Receptors, G-Protein-Coupled, Mice, Plaque, Amyloid

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