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.

Topological analyses in APP/PS1 mice reveal that astrocytes do not migrate to amyloid-β plaques

“…This belief contends that as part of the innate immune defense astrocytes migrate to plaques, phagocytose fibrillar amyloid-β, and seal plaque-induced injury with a scar, thereby reducing the growth of plaques and their overall impact. This is based on two pieces of evidence: Astrocytes can migrate to and clear plaques ex vivo (20,21), and impairment of astrocyte activation by deletion of genes encoding for GFAP and vimentin results in increased plaque load in APP/PS1 mice (22). Alternative interpretations of this evidence include the possibilities that (i) ex vivo astrocytes come from cultured astrocytes and hence have plastic properties and an ability to migrate that adult astrocytes lack in situ (23), and (ii) gfap and vimentin deletion may abrogate both the capacity of astrocytes to react to injury and also basic functions, for example the clearing of soluble amyloid-β by the LDL receptor in an ApoE-dependent manner (24).…”

Astrocyte Reactivity and Reactive Astrogliosis: Costs and Benefits

“…The same conclusion was made by exposing the GFAP Ϫ/Ϫ Vim Ϫ/Ϫ mice to focal brain ischemia (induced by the transection of the middle cerebral artery), a mouse model of ischemic stroke, which resulted in larger infarction compared with wild-type mice (132). The underlying cellular and molecular mechanisms remain incompletely understood, although the astrocyte IF system has been linked to astrocyte motility (131); viscoelastic properties, which might affect cell migration (139); vesicle trafficking (184,185,241); activation of Erk and c-fos (156); the efficiency of glutamate transport and astrocyte gap junctional communication (132) (135); response to hypoosmotic and oxidative stress and neuroprotective properties (55,58); reconstruction of blood-brain barrier (177); MHC class II molecule presentation (241); and interaction with microglia (125,143). The functions of astrocytes in healthy CNS and in acute and late stages of neurological diseases are exemplified in FIGURE 8C.…”

“…Whereas both microglia and astrocytes around amyloid plaques show increased immunoproteasome expression (164), amyloid deposition is associated with increased proliferation of microglia but not reactive astrocytes (109,217). When GFAP Ϫ/Ϫ Vim Ϫ/Ϫ mice that exhibit attenuated reactive astrogliosis were crossed with a mouse model of AD-like pathology (transgenic mice expressing mutant human amyloid precursor protein and presenilin-1), the progression of neuropathological changes was facilitated, with increased plaque load and more abundant dystrophic neurites (FIGURE 9A) (125). Amyloid precursor protein expression and processing were both normal, which implies that reactive astrocytes affect plaque dynamics through interaction with amyloid plaques but not via synthesis or metabolism of amyloid protein.…”

Plaque-Associated Local Toxicity Increases over the Clinical Course of Alzheimer Disease

“…The American Journal of Pathology -ajp.amjpathol.orgneurites per plaque, 65 whereas depopulation of microglia has no effect on dystrophic neurites. 66 Anti-Ab immunization was successful at reducing plaque deposition in AD mouse models and in the handful of human patients who have come to autopsy, but substantial clinical benefit or at least stabilization of cognitive decline has not been observed.…”