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Progranulin protects against amyloid β deposition and toxicity in Alzheimer's disease mouse models.

TitleProgranulin protects against amyloid β deposition and toxicity in Alzheimer's disease mouse models.
Publication TypeJournal Article
Year of Publication2014
AuthorsS Minami S, Min S-W, Krabbe G, Wang C, Zhou Y, Asgarov R, Li Y, Martens LH, Elia LP, Ward ME, Mucke L, Farese RV, Gan L
JournalNat Med
Volume20
Issue10
Pagination1157-64
Date Published2014 Oct
ISSN1546-170X
KeywordsAlzheimer Disease, Amyloid beta-Peptides, Animals, Brain, Cognition, Disease Models, Animal, Female, Frontotemporal Lobar Degeneration, Gene Expression Regulation, Humans, Immunity, Innate, Intercellular Signaling Peptides and Proteins, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Microglia, Phagocytosis, Plaque, Amyloid, Rats, Up-Regulation
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.

DOI10.1038/nm.3672
Alternate JournalNat. Med.
PubMed ID25261995
PubMed Central IDPMC4196723
Grant ListP50 AG023501 / AG / NIA NIH HHS / United States
F31AG034793 / AG / NIA NIH HHS / United States
1R01AG036884 / AG / NIA NIH HHS / United States
R01 AG036884 / AG / NIA NIH HHS / United States
R01AG030207 / AG / NIA NIH HHS / United States
F32 NS076239 / NS / NINDS NIH HHS / United States
P30NS065780 / NS / NINDS NIH HHS / United States
F32NS076239 / NS / NINDS NIH HHS / United States