Review: Astrocytes in Alzheimer's disease and other age‐associated dementias

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The neurone is the target for many of the cellular pathologies of dementia, such as neurofibrillary tangles (NFTs) and Lewy bodies, while extracellular beta‐amyloid (Aβ) may also target neurones and their processes. These classical pathologies remain central to theories of dementia pathogenesis and to neuropathological diagnosis, and much of the focus in dementia research has been on the neurone. However, although important correlates of dementia, other factors may also be Relevant. Population‐based studies such as the UK Medical Research Council Cognitive Function and Ageing Study (CFAS), and other large autopsy series, have shown that classical neuropathological lesions alone do not account for all of dementia in statistical models, particularly at the oldest ages 1. This is also recognized in clinical trials with the identification of individuals with Alzheimer's disease (AD)‐like clinical presentations but with little pathology on amyloid imaging or on neuropathology, so‐called AD with insufficient neuropathology 9. Different molecular forms of amyloid, tau and other protein pathologies are important ongoing areas of therapeutic targets, but other factors may contribute to age‐related cognitive decline either independently or by modulating the effect of the classical cellular and molecular pathologies on neuronal fate and function. This includes other cell types and the interactions between them.
Neurones function within the context of other cell types, and recent theories have emphasized the importance of dysfunction of the neurovascular unit (NVU) in ageing and in the development of neurodegeneration and dementia 10. The NVU includes the neurone, the microvasculature composed of endothelial cells and pericytes, astrocytes and the blood–brain barrier (BBB). Oligodendrocytes and microglia are additional key components. A neurovascular hypothesis of dementia would then seek to integrate changes in the neurone with alterations of other cell types and their interaction within the NVU.
Long thought of as ‘just’ a supporting cell, or brain glue, the astrocyte has important physiological roles in relation to the neurone, to synaptic function and to BBB and neurovascular coupling. Astrocyte dysfunction may therefore be an important contributor to dysfunction of the NVU, with effects on neurones and the microvasculature. This review is focused on the role of the astrocyte in the brain and how perturbation of its function may contribute to dementia pathogenesis, particularly focusing on AD.

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