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

Abstract

Although the clustering of GFAP immunopositive astrocytes around amyloid-β plaques in Alzheimer's disease has led to the widespread assumption that plaques attract astrocytes, recent studies suggest that astrocytes stay put in injury. Here we reexamine astrocyte migration to plaques, using quantitative spatial analysis and computer modeling to investigate the topology of astrocytes in 3D images obtained by two-photon microscopy of living APP/PS1 mice and WT littermates. In WT mice, cortical astrocyte topology fits a model in which a liquid of hard spheres exclude each other in a confined space. Plaques do not disturb this arrangement except at very large plaque loads, but, locally, cause subtle outward shifts of the astrocytes located in three tiers around plaques. These data suggest that astrocytes respond to plaque-induced neuropil injury primarily by changing phenotype, and hence function, rather than location.T he role of astrocytes in amyloid-β deposition during Alzheimer's disease-whether they prevent, potentiate, or have no effect on plaque formation-remains unknown. The peer-reviewed literature indicates that it is widely believed that amyloid-β plaques attract astrocytes, with statements such as "astrocytes migrate to amyloid-β plaques," "amyloid-β plaques recruit astrocytes," and variations thereof frequently appearing. The idea that astrocytes are attracted to plaques is an extension of the notion that astrocytes migrate to zones of injury (1, 2) and is mostly based on the immunohistochemical observation that amyloid-β deposits are typically surrounded by concentric rings of "reactive astrocytes," defined by increased GFAP immunoreactivity and hypertrophy. However, recent studies question the capacity of astrocytes to move (3, 4). These suggest instead that astrocytes may be restricted to their birthplace (3), which in the neocortex seems to be within neuronal columns derived from radial glia (5). Recent stereological assessments of astrocytes in Alzheimer's disease suggest that their most prominent change is phenotypic (i.e., GFAP immunoreactivity and hypertrophy) rather than proliferative (6). Thus, doubts have risen over the recruitment of astrocytes by plaques.Using the APPSwe/PS1dE9 (APP/PS1) double-transgenic mouse model of Alzheimer's disease, we revisited the idea that astrocytes migrate to plaques. Our approach improved on the traditional GFAP immunohistochemical analysis postmortem in three ways. First, the analyses were performed in 3D reconstructions of images captured in vivo through cranial windows by two-photon microscopy. These materials are superior to sectioned specimens from fixed brains because they preserve true spatial relationships in 3D to great depths (up to 200 μm from the cortical surface), providing accurate positional information for each astrocyte. Second, astrocytes were labeled with sulforhodamine 101 (SR101), a selective fluorescent marker of reactive and nonreactive astrocytes (7), thus avoiding the bias of identifying only a subset of astrocytes as with GFAP. Third, ...

Characterization of astrocytes throughout life in wildtype and APP/PS1 mice after early-life stress exposure

“…The reduction in global versus the increase in clustered GFAP coverage is in line with a previous study where general astroglial cytoskeletal atrophy was observed, while GFAP+ astrocytes surrounding Aβ plaques were hypertrophic in the HPC of 18-month-old 3xTG AD mice [77]. Given that astrocytes do not migrate to amyloid plaques [78], current data suggests that astrocytes near plaques are induced to upregulate GFAP expression, while astrocytes in the rest of the HPC downregulate GFAP. As many extracellular factors, e.g., inflammatory factors, can affect transcription and translation of GFAP [79,80], microenvironmental changes induced by plaque accumulation may lead to local dynamic alterations in GFAP expression.…”

Characterization of astrocytes throughout life in wildtype and APP/PS1 mice after early-life stress exposure

“…The reduction in global versus the increase in clustered GFAP coverage is in line with a previous study where general astroglial cytoskeletal atrophy was observed, while GFAP+ astrocytes surrounding Aβ plaques were hypertrophic in the HPC of 18-month-old 3xTG AD mice [77]. Given that astrocytes do not migrate to amyloid plaques [78], current data suggests that astrocytes near plaques are induced to upregulate GFAP expression, while astrocytes in the rest of the HPC downregulate GFAP. As many extracellular factors, e.g.…”

Characterization of astrocytes throughout life in wildtype and APP/PS1 mice after early-life stress exposure

“…The reduction in global versus the increase in clustered GFAP coverage is in line with a previous study where general astroglial cytoskeletal atrophy was observed, while GFAP + astrocytes surrounding Aβ plaques were hypertrophic in the HPC of 18-month-old 3xTG AD mice [76]. Given that astrocytes do not migrate to amyloid plaques [77], current data suggests that astrocytes near plaques are induced to upregulate GFAP expression, while astrocytes in the rest of the HPC downregulate GFAP. As many extracellular factors, e.g.…”