title: Reducing inflammation and rescuing FTD-related behavioral deficits in progranulin-deficient mice with α7 nicotinic acetylcholine receptor agonists.
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.
authors.affiliation: Gladstone Institute of Neurological Diseases, 1650 Owens St., San Francisco, CA 94158, United States; Department of Neurology, University of California, San Francisco, CA 94158, United States.
authors.forename: S Sakura
authors.initials: SS
authors.lastname: Minami
authors.affiliation: Gladstone Institute of Neurological Diseases, 1650 Owens St., San Francisco, CA 94158, United States.
authors.forename: Vivian
authors.initials: V
authors.lastname: Shen
authors.affiliation: Gladstone Institute of Neurological Diseases, 1650 Owens St., San Francisco, CA 94158, United States.
authors.forename: David
authors.initials: D
authors.lastname: Le
authors.affiliation: Gladstone Institute of Neurological Diseases, 1650 Owens St., San Francisco, CA 94158, United States; Department of Neurology, University of California, San Francisco, CA 94158, United States.
authors.forename: Grietje
authors.initials: G
authors.lastname: Krabbe
authors.affiliation: Gladstone Institute of Neurological Diseases, 1650 Owens St., San Francisco, CA 94158, United States; Graduate Program in Neurochemistry and Molecular Neurobiology, Stockholm University, Sweden.
authors.forename: Rustam
authors.initials: R
authors.lastname: Asgarov
authors.affiliation: Gladstone Institute of Neurological Diseases, 1650 Owens St., San Francisco, CA 94158, United States.
authors.forename: Liberty
authors.initials: L
authors.lastname: Perez-Celajes
authors.affiliation: AbbVie Inc., North Chicago, IL 60064, United States.
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Lee
authors.affiliation: AbbVie Inc., North Chicago, IL 60064, United States.
authors.forename: Jinhe
authors.initials: J
authors.lastname: Li
authors.affiliation: AbbVie Inc., North Chicago, IL 60064, United States.
authors.forename: Diana
authors.initials: D
authors.lastname: Donnelly-Roberts
authors.affiliation: Gladstone Institute of Neurological Diseases, 1650 Owens St., San Francisco, CA 94158, United States; Department of Neurology, University of California, San Francisco, CA 94158, United States. Electronic address: lgan@gladstone.ucsf.edu.
authors.forename: Li
authors.initials: L
authors.lastname: Gan
mesh_terms: D000818:Animals; D001372:Aza Compounds / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D004147:Dioxins / Q000627:therapeutic use*; D005260:Female; D057180:Frontotemporal Dementia / Q000188:drug therapy*; D017930:Genes, Reporter; D000077155:Granulins; D007211:Indoles / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D000077153:Progranulins; D011812:Quinuclidines / Q000627:therapeutic use*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists*
chemical_list: C552256:5-(6-(1-azabicyclo(2,2,2)oct-3-yloxy)pyridazin-3-yl)-1H-indole; D001372:Aza Compounds; D004147:Dioxins; D000077155:Granulins; C120204:Grn protein, mouse; D007211:Indoles; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; C514026:PHA-568487E; D000077153:Progranulins; D011812:Quinuclidines; D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords: Frontotemporal dementia; Inflammation; Microglial activation; Nicotine; Progranulin