| Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice. | |
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MedLine Citation:
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PMID: 23038755 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The accumulation of aggregated amyloid-β (Aβ) in amyloid plaques is a neuropathological hallmark of Alzheimer's disease (AD). Reactive astrocytes are intimately associated with amyloid plaques; however, their role in AD pathogenesis is unclear. We deleted the genes encoding two intermediate filament proteins required for astrocyte activation-glial fibrillary acid protein (Gfap) and vimentin (Vim)-in transgenic mice expressing mutant human amyloid precursor protein and presenilin-1 (APP/PS1). The gene deletions increased amyloid plaque load: APP/PS1 Gfap(-/-)Vim(-/-) mice had twice the plaque load of APP/PS1 Gfap(+/+)Vim(+/+) mice at 8 and 12 mo of age. APP expression and soluble and interstitial fluid Aβ levels were unchanged, suggesting that the deletions had no effect on APP processing or Aβ generation. Astrocyte morphology was markedly altered by the deletions: wild-type astrocytes had hypertrophied processes that surrounded and infiltrated plaques, whereas Gfap(-/-)Vim(-/-) astrocytes had little process hypertrophy and lacked contact with adjacent plaques. Moreover, Gfap and Vim gene deletion resulted in a marked increase in dystrophic neurites (2- to 3-fold higher than APP/PS1 Gfap(+/+)Vim(+/+) mice), even after normalization for amyloid load. These results suggest that astrocyte activation limits plaque growth and attenuates plaque-related dystrophic neurites. These activities may require intimate contact between astrocyte and plaque. |
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Authors:
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Andrew W Kraft; Xiaoyan Hu; Hyejin Yoon; Ping Yan; Qingli Xiao; Yan Wang; So Chon Gil; Jennifer Brown; Ulrika Wilhelmsson; Jessica L Restivo; John R Cirrito; David M Holtzman; Jungsu Kim; Milos Pekny; Jin-Moo Lee |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-10-04 |
Journal Detail:
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Title: FASEB journal : official publication of the Federation of American Societies for Experimental Biology Volume: 27 ISSN: 1530-6860 ISO Abbreviation: FASEB J. Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-01-03 Completed Date: 2013-03-07 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 8804484 Medline TA: FASEB J Country: United States |
Other Details:
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Languages: eng Pagination: 187-98 Citation Subset: IM |
Affiliation:
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The Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63124, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amyloid beta-Protein Precursor
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genetics* Animals Astrocytes / cytology* Blotting, Western Enzyme-Linked Immunosorbent Assay Immunohistochemistry Mice Presenilin-1 / genetics* Real-Time Polymerase Chain Reaction |
| Grant Support | |
ID/Acronym/Agency:
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P01 NS32636/NS/NINDS NIH HHS; P30NS69329/NS/NINDS NIH HHS; R01 NS48283/NS/NINDS NIH HHS; R01 NS67905/NS/NINDS NIH HHS; R37 AG13956/AG/NIA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Amyloid beta-Protein Precursor; 0/Presenilin-1 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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