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Progranulin protects against amyloid ß deposition and toxicity in Alzheimer's disease mouse models.
Minami, S Sakura; Min, Sang-Won; Krabbe, Grietje; Wang, Chao; Zhou, Yungui; Asgarov, Rustam; Li, Yaqiao; Martens, Lauren H; Elia, Lisa P; Ward, Michael E; Mucke, Lennart; Farese, Robert V; Gan, Li.
Afiliação
  • Minami SS; 1] Gladstone Institute of Neurological Disease, San Francisco, California, USA. [2] Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
  • Min SW; 1] Gladstone Institute of Neurological Disease, San Francisco, California, USA. [2] Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
  • Krabbe G; 1] Gladstone Institute of Neurological Disease, San Francisco, California, USA. [2] Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
  • Wang C; 1] Gladstone Institute of Neurological Disease, San Francisco, California, USA. [2] Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
  • Zhou Y; Gladstone Institute of Neurological Disease, San Francisco, California, USA.
  • Asgarov R; Graduate Program in Neurochemistry with Molecular Neurobiology, Stockholm University, Stockholm, Sweden.
  • Li Y; Gladstone Institute of Neurological Disease, San Francisco, California, USA.
  • Martens LH; Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA.
  • Elia LP; Gladstone Institute of Neurological Disease, San Francisco, California, USA.
  • Ward ME; 1] Gladstone Institute of Neurological Disease, San Francisco, California, USA. [2] Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
  • Mucke L; 1] Gladstone Institute of Neurological Disease, San Francisco, California, USA. [2] Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
  • Farese RV; 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, US
  • Gan L; 1] Gladstone Institute of Neurological Disease, San Francisco, California, USA. [2] Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
Nat Med ; 20(10): 1157-64, 2014 Oct.
Article em En | MEDLINE | ID: mdl-25261995
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 ß (Aß) 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. Aß plaque load correlated negatively with levels of hippocampal PGRN, showing the dose-dependent inhibitory effects of PGRN on plaque deposition. PGRN also protected against Aß toxicity. Lentivirus-mediated PGRN overexpression prevented spatial memory deficits and hippocampal neuronal loss in AD mice. The protective effects of PGRN against Aß deposition and toxicity have important therapeutic implications. We propose enhancing PGRN as a potential treatment for PGRN-deficient FTLD and AD.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Peptídeos beta-Amiloides / Peptídeos e Proteínas de Sinalização Intercelular / Doença de Alzheimer Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2014 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Peptídeos beta-Amiloides / Peptídeos e Proteínas de Sinalização Intercelular / Doença de Alzheimer Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2014 Tipo de documento: Article