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Nat Med. 2014 Oct;20(10):1157-64. doi: 10.1038/nm.3672. Epub 2014 Sep 28.

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

Author information

1
1] Gladstone Institute of Neurological Disease, San Francisco, California, USA. [2] Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
2
Gladstone Institute of Neurological Disease, San Francisco, California, USA.
3
Graduate Program in Neurochemistry with Molecular Neurobiology, Stockholm University, Stockholm, Sweden.
4
Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA.
5
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.

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.

PMID:
25261995
PMCID:
PMC4196723
DOI:
10.1038/nm.3672
[Indexed for MEDLINE]
Free PMC Article

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