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Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice.

Journal article
Authors 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
Published in FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume 27
Issue 1
Pages 187-98
ISSN 1530-6860
Publication year 2013
Published at Institute of Neuroscience and Physiology, Department of Clinical Neuroscience and Rehabilitation
Pages 187-98
Language en
Links dx.doi.org/10.1096/fj.12-208660
Subject categories Basic Medicine, Neurobiology

Abstract

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.-Kraft, A. W., Hu, X., Yoon, H., Yan, P., Xiao, Q., Wang, Y., Gil, S. C., Brown, J., Wilhelmsson, U., Restivo, J. L., Cirrito, J. R., Holtzman, D. M., Kim, J., Pekny, M., Lee, J.-M. Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice.

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