title: Progranulin protects against amyloid β deposition and toxicity in Alzheimer's disease mouse models.
abstract: Haploinsufficiency of the progranulin (PGRN) gene (GRN) causes familial frontotemporal lobar degeneration (FTLD) and modulates an innate immune response in humans and in mouse models. GRN polymorphism may be linked to late-onset Alzheimer's disease (AD). However, the role of PGRN in AD pathogenesis is unknown. Here we show that PGRN inhibits amyloid β (Aβ) deposition. Selectively reducing microglial expression of PGRN in AD mouse models impaired phagocytosis, increased plaque load threefold and exacerbated cognitive deficits. Lentivirus-mediated PGRN overexpression lowered plaque load in AD mice with aggressive amyloid plaque pathology. Aβ plaque load correlated negatively with levels of hippocampal PGRN, showing the dose-dependent inhibitory effects of PGRN on plaque deposition. PGRN also protected against Aβ toxicity. Lentivirus-mediated PGRN overexpression prevented spatial memory deficits and hippocampal neuronal loss in AD mice. The protective effects of PGRN against Aβ deposition and toxicity have important therapeutic implications. We propose enhancing PGRN as a potential treatment for PGRN-deficient FTLD and AD.
authors.affiliation: 1] Gladstone Institute of Neurological Disease, San Francisco, California, USA. [2] Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: S Sakura
authors.initials: SS
authors.lastname: Minami
authors.affiliation: 1] Gladstone Institute of Neurological Disease, San Francisco, California, USA. [2] Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Sang-Won
authors.initials: SW
authors.lastname: Min
authors.affiliation: 1] Gladstone Institute of Neurological Disease, San Francisco, California, USA. [2] Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Grietje
authors.initials: G
authors.lastname: Krabbe
authors.affiliation: 1] Gladstone Institute of Neurological Disease, San Francisco, California, USA. [2] Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California, USA.
authors.forename: Yungui
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Graduate Program in Neurochemistry with Molecular Neurobiology, Stockholm University, Stockholm, Sweden.
authors.forename: Rustam
authors.initials: R
authors.lastname: Asgarov
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California, USA.
authors.forename: Yaqiao
authors.initials: Y
authors.lastname: Li
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA.
authors.forename: Lauren H
authors.initials: LH
authors.lastname: Martens
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California, USA.
authors.forename: Lisa P
authors.initials: LP
authors.lastname: Elia
authors.affiliation: 1] Gladstone Institute of Neurological Disease, San Francisco, California, USA. [2] Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Ward
authors.affiliation: 1] Gladstone Institute of Neurological Disease, San Francisco, California, USA. [2] Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Lennart
authors.initials: L
authors.lastname: Mucke
authors.affiliation: 1] Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA. [2] Department of Medicine, University of California, San Francisco, San Francisco, California, USA. [3] Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Robert V
authors.initials: RV
authors.lastname: Farese
authors.affiliation: 1] Gladstone Institute of Neurological Disease, San Francisco, California, USA. [2] Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Gan
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003071:Cognition / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D005786:Gene Expression Regulation; D000077155:Granulins; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D010587:Phagocytosis; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D000077153:Progranulins; D051381:Rats; D015854:Up-Regulation
chemical_list: D016229:Amyloid beta-Peptides; C492314:GRN protein, human; D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins