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Reducing inflammation and rescuing FTD-related behavioral deficits in progranulin-deficient mice with alpha 7 nicotinic acetylcholine receptor agonists
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Number of Authors: 102015 (English)In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 97, no 4, p. 454-462Article in journal (Refereed) Published
Abstract [en]

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 alpha 7 nAChR agonists reduces neuroinflammation. Here, we investigated whether activation of nAChRs by nicotine or alpha 7 agonists improved the excessive inflammatory and behavioral phenotypes of a progranulin-deficient FTD mouse model. We found that treatment with selective alpha 7 agonists, PHA-568487 or ABT-107, strongly suppressed the activation of NF-kappa B in progranulin-deficient cells. Treatment with ABT-107 also reduced microgliosis, decreased TNF alpha levels, and reduced compulsive behavior in progranulin-deficient mice. Collectively, these data suggest that targeting activation of the alpha 7 nAChR pathway may be beneficial in decreasing neuroinflammation and reversing some of the behavioral deficits observed in progranulin-deficient FTD.

Place, publisher, year, edition, pages
2015. Vol. 97, no 4, p. 454-462
Keywords [en]
Frontotemporal dementia, Progranulin, Nicotine, Inflammation, Microglial activation
National Category
Pharmacology and Toxicology Immunology in the medical area
Identifiers
URN: urn:nbn:se:su:diva-159638DOI: 10.1016/j.bcp.2015.07.016ISI: 000363437200012PubMedID: 26206194OAI: oai:DiVA.org:su-159638DiVA, id: diva2:1245443
Available from: 2018-09-05 Created: 2018-09-05 Last updated: 2018-09-05Bibliographically approved

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