title: Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice.
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.
authors.affiliation: 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.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Kraft
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Hu
authors.forename: Hyejin
authors.initials: H
authors.lastname: Yoon
authors.forename: Ping
authors.initials: P
authors.lastname: Yan
authors.forename: Qingli
authors.initials: Q
authors.lastname: Xiao
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: So Chon
authors.initials: SC
authors.lastname: Gil
authors.forename: Jennifer
authors.initials: J
authors.lastname: Brown
authors.forename: Ulrika
authors.initials: U
authors.lastname: Wilhelmsson
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Restivo
authors.forename: John R
authors.initials: JR
authors.lastname: Cirrito
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.forename: Jungsu
authors.initials: J
authors.lastname: Kim
authors.forename: Milos
authors.initials: M
authors.lastname: Pekny
authors.forename: Jin-Moo
authors.initials: JM
authors.lastname: Lee
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001253:Astrocytes / Q000166:cytology*; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D051379:Mice; D053764:Presenilin-1 / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1