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Reducing inflammation and rescuing FTD-related behavioral deficits in progranulin-deficient mice with α7 nicotinic acetylcholine receptor agonists.

TitleReducing inflammation and rescuing FTD-related behavioral deficits in progranulin-deficient mice with α7 nicotinic acetylcholine receptor agonists.
Publication TypeJournal Article
Year of Publication2015
AuthorsS Minami S, Shen V, Le D, Krabbe G, Asgarov R, Perez-Celajes L, Lee C-H, Li J, Donnelly-Roberts D, Gan L
JournalBiochem Pharmacol
Volume97
Issue4
Pagination454-462
Date Published2015 Oct 15
ISSN1873-2968
Keywordsalpha7 Nicotinic Acetylcholine Receptor, Animals, Aza Compounds, Behavior, Animal, Dioxins, Female, Frontotemporal Dementia, Genes, Reporter, Indoles, Inflammation, Intercellular Signaling Peptides and Proteins, Macrophages, Male, Mice, Mice, Knockout, Microglia, NF-kappa B, Quinuclidines
Abstract

Mutations in the progranulin gene cause frontotemporal dementia (FTD), a debilitating neurodegenerative disease that involves atrophy of the frontal and temporal lobes and affects personality, behavior, and language. Progranulin-deficient mouse models of FTD exhibit deficits in compulsive and social behaviors reminiscent of patients with FTD, and develop excessive microgliosis and increased release of inflammatory cytokines. Activation of nicotinic acetylcholine receptors (nAChRs) by nicotine or specific α7 nAChR agonists reduces neuroinflammation. Here, we investigated whether activation of nAChRs by nicotine or α7 agonists improved the excessive inflammatory and behavioral phenotypes of a progranulin-deficient FTD mouse model. We found that treatment with selective α7 agonists, PHA-568487 or ABT-107, strongly suppressed the activation of NF-κB in progranulin-deficient cells. Treatment with ABT-107 also reduced microgliosis, decreased TNFα levels, and reduced compulsive behavior in progranulin-deficient mice. Collectively, these data suggest that targeting activation of the α7 nAChR pathway may be beneficial in decreasing neuroinflammation and reversing some of the behavioral deficits observed in progranulin-deficient FTD.

DOI10.1016/j.bcp.2015.07.016
Alternate JournalBiochem. Pharmacol.
PubMed ID26206194
PubMed Central IDPMC4859338
Grant List1R01AG036884 / AG / NIA NIH HHS / United States
R01 AG036884 / AG / NIA NIH HHS / United States
R01AG030207 / AG / NIA NIH HHS / United States
P30 NS065780 / NS / NINDS NIH HHS / United States
F32 NS076239 / NS / NINDS NIH HHS / United States
R01 AG030207 / AG / NIA NIH HHS / United States
R01 AG051390 / AG / NIA NIH HHS / United States
CO6 RRO18928 / CO / NCI NIH HHS / United States
F32NS076239 / NS / NINDS NIH HHS / United States