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

被引：185

作者：

Minami, S. Sakura ^{[1
,2
]}

Min, Sang-Won ^{[1
,2
]}

Krabbe, Grietje ^{[1
,2
]}

Wang, Chao ^{[1
,2
]}

Zhou, Yungui ^{[1
]}

Asgarov, Rustam ^{[3
]}

Li, Yaqiao ^{[1
]}

Martens, Lauren H. ^{[4
]}

Elia, Lisa P. ^{[1
]}

Ward, Michael E. ^{[1
,2
]}

Mucke, Lennart ^{[1
,2
]}

Farese, Robert V., Jr. ^{[4
,5
,6
]}

Gan, Li ^{[1
,2
]}

机构：

[1] Gladstone Inst Neurol Dis, San Francisco, CA 94158 USA

[2] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA

[3] Stockholm Univ, Grad Program Neurochem Mol Neurobiol, S-10691 Stockholm, Sweden

[4] Gladstone Inst Cardiovasc Dis, San Francisco, CA USA

[5] Univ Calif San Francisco, Dept Med, San Francisco, CA USA

[6] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA

来源：

NATURE MEDICINE | 2014年 / 20卷 / 10期

基金：

美国国家卫生研究院;

关键词：

NEURON LOSS; MICROGLIAL PHAGOCYTOSIS; TRANSGENIC MICE; INFLAMMATION; EXPRESSION; MUTATIONS; BRAIN; NEUROINFLAMMATION; ACCUMULATION; DYSFUNCTION;

D O I：

10.1038/nm.3672

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 beta (A beta) 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. A beta plaque load correlated negatively with levels of hippocampal PGRN, showing the dose-dependent inhibitory effects of PGRN on plaque deposition. PGRN also protected against A beta toxicity. Lentivirus-mediated PGRN overexpression prevented spatial memory deficits and hippocampal neuronal loss in AD mice. The protective effects of PGRN against A beta deposition and toxicity have important therapeutic implications. We propose enhancing PGRN as a potential treatment for PGRN-deficient FTLD and AD.

引用

页码：1157 / 1164

页数：8

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