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Progranulin Protects against Amyloid β Deposition and Toxicity in Alzheimer’s Disease Mouse Models
Haploinsufficiency of progranulin (PGRN) gene (GRN) causes familial frontotemporal lobar degeneration (FTLD), and modulates an innate immune response in humans and mouse models. GRN polymorphism may be linked to late-onset Alzheimer’s disease (AD). However, PRGN’s role in AD pathogenesis is unknown....
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4196723/ https://www.ncbi.nlm.nih.gov/pubmed/25261995 http://dx.doi.org/10.1038/nm.3672 |
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author | 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 |
author_facet | 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 |
author_sort | Minami, S. Sakura |
collection | PubMed |
description | Haploinsufficiency of progranulin (PGRN) gene (GRN) causes familial frontotemporal lobar degeneration (FTLD), and modulates an innate immune response in humans and mouse models. GRN polymorphism may be linked to late-onset Alzheimer’s disease (AD). However, PRGN’s role in AD pathogenesis is unknown. Here, we show PGRN inhibits amyloid β (Aβ) deposition. Selectively reducing microglial PGRN in AD mice impaired phagocytosis and increased plaque load threefold. 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 PGRN’s dose-dependent inhibitory effects on plaque deposition. PGRN also protected against Aβ toxicity. Reducing microglial PGRN exacerbated cognitive deficits in AD mice. Lentivirus-mediated PGRN overexpression prevented spatial memory deficits and hippocampal neuronal loss in AD mice. PGRN’s protective effects against Aβ deposition and toxicity have important therapeutic implications. We propose enhancing PGRN as a potential treatment for PGRN-deficient FTD and AD. |
format | Online Article Text |
id | pubmed-4196723 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
record_format | MEDLINE/PubMed |
spelling | pubmed-41967232015-04-01 Progranulin Protects against Amyloid β 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 Nat Med Article Haploinsufficiency of progranulin (PGRN) gene (GRN) causes familial frontotemporal lobar degeneration (FTLD), and modulates an innate immune response in humans and mouse models. GRN polymorphism may be linked to late-onset Alzheimer’s disease (AD). However, PRGN’s role in AD pathogenesis is unknown. Here, we show PGRN inhibits amyloid β (Aβ) deposition. Selectively reducing microglial PGRN in AD mice impaired phagocytosis and increased plaque load threefold. 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 PGRN’s dose-dependent inhibitory effects on plaque deposition. PGRN also protected against Aβ toxicity. Reducing microglial PGRN exacerbated cognitive deficits in AD mice. Lentivirus-mediated PGRN overexpression prevented spatial memory deficits and hippocampal neuronal loss in AD mice. PGRN’s protective effects against Aβ deposition and toxicity have important therapeutic implications. We propose enhancing PGRN as a potential treatment for PGRN-deficient FTD and AD. 2014-09-28 2014-10 /pmc/articles/PMC4196723/ /pubmed/25261995 http://dx.doi.org/10.1038/nm.3672 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article 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 Progranulin Protects against Amyloid β Deposition and Toxicity in Alzheimer’s Disease Mouse Models |
title | Progranulin Protects against Amyloid β Deposition and Toxicity in Alzheimer’s Disease Mouse Models |
title_full | Progranulin Protects against Amyloid β Deposition and Toxicity in Alzheimer’s Disease Mouse Models |
title_fullStr | Progranulin Protects against Amyloid β Deposition and Toxicity in Alzheimer’s Disease Mouse Models |
title_full_unstemmed | Progranulin Protects against Amyloid β Deposition and Toxicity in Alzheimer’s Disease Mouse Models |
title_short | Progranulin Protects against Amyloid β Deposition and Toxicity in Alzheimer’s Disease Mouse Models |
title_sort | progranulin protects against amyloid β deposition and toxicity in alzheimer’s disease mouse models |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4196723/ https://www.ncbi.nlm.nih.gov/pubmed/25261995 http://dx.doi.org/10.1038/nm.3672 |
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