Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice

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

Research output: Contribution to journalArticle

154 Scopus citations

Abstract

The accumulation of aggregated amy-loid-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.

Original languageEnglish (US)
Pages (from-to)187-198
Number of pages12
JournalFASEB Journal
Volume27
Issue number1
DOIs
StatePublished - Jan 1 2013

    Fingerprint

Keywords

  • Alzheimer's disease
  • Astrogliosis
  • GFAP
  • Intermediate filaments
  • Vimentin

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

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. (2013). Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice. FASEB Journal, 27(1), 187-198. https://doi.org/10.1096/fj.12-208660