Abstract
Reactive astrocytes were identified as a component of senile amyloid plaques in the cortex of Alzheimer’s disease (AD) patients several decades ago. However, their role in AD pathophysiology has remained elusive ever since, in part owing to the extrapolation of the literature from primary astrocyte cultures and acute brain injury models to a chronic neurodegenerative scenario. Recent accumulating evidence supports the idea that reactive astrocytes in AD acquire neurotoxic properties, likely due to both a gain of toxic function and a loss of their neurotrophic effects. However, the diversity and complexity of this glial cell is only beginning to be unveiled, anticipating that astrocyte reaction might be heterogeneous as well. Herein we review the evidence from mouse models of AD and human neuropathological studies and attempt to decipher the main conundrums that astrocytes pose to our understanding of AD development and progression. We discuss the morphological features that characterize astrocyte reaction in the AD brain, the consequences of astrocyte reaction for both astrocyte biology and AD pathological hallmarks, and the molecular pathways that have been implicated in this reaction.
Highlights
The term ‘‘glia’’ was first coined by Virchow to refer to the non-neuronal cells that form the ‘‘glue’’ of the brain (Virchow, 1858)
With regards to aquaporin 4 (AQ4), no significant differences in protein levels were found between Alzheimer’s disease (AD) and healthy control subjects by Western blot (Pérez et al, 2007), but an enhanced immunoreactivity associated with amyloid plaques and cerebral amyloid angiopathy (CAA) has been reported by other authors (Moftakhar et al, 2010; Hoshi et al, 2012), suggesting the possibility of a redistribution of AQ4 within astrocytes in AD
Since astrocyte reaction appears to be linked to the neurodegenerative process in AD, it follows that imaging and cerebrospinal fluid (CSF) biomarkers of astrocyte reaction could be useful to improve the accuracy of the clinical diagnosis of AD dementia and monitor and predict the progression of the disease
Summary
The term ‘‘glia’’ was first coined by Virchow to refer to the non-neuronal cells that form the ‘‘glue’’ of the brain (Virchow, 1858). Soon after the development of appropriate staining methods, it became apparent that both acute (i.e., traumatic brain or spinal cord injury, stroke) and chronic (epilepsy, neurodegenerative diseases) insults to the central nervous system (CNS) are associated with a dramatic change in astrocyte morphology. In these conditions astrocytes appear hypertrophic and overexpress two intermediate-filament proteins of their cytoskeleton: glial fibrillar acidic protein (GFAP) and vimentin. These two characteristics qualify the astrocytes as ‘‘reactive’’, as opposed to ‘‘resting’’ non-reactive astrocytes, which are not truly quiescent but exert many of the functions listed below. We will highlight the main ongoing scientific controversies and the remaining areas of uncertainty
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