Astrocyte adaptation in Alzheimer's disease: a focus on astrocytic P2X₇R

Astrocytes are key homeostatic and defensive cells of the central nervous system (CNS). They undertake numerous functions during development and in adulthood to support and protect the brain through finely regulated communication with other cellular elements of the nervous tissue. In Alzheimer's disease (AD), astrocytes undergo heterogeneous morphological, molecular and functional alterations represented by reactive remodelling, asthenia and loss of function. Reactive astrocytes closely associate with amyloid β (Aβ) plaques and neurofibrillary tangles in advanced AD. The specific contribution of astrocytes to AD could potentially evolve along the disease process and includes alterations in their signalling, interactions with pathological protein aggregates, metabolic and synaptic impairments. In this review, we focus on the purinergic receptor, P2X₇R, and discuss the evidence that P2X₇R activation contributes to altered astrocyte functions in AD. Expression of P2X₇R is increased in AD brain relative to non-demented controls, and animal studies have shown that P2X₇R antagonism improves cognitive and synaptic impairments in models of amyloidosis and tauopathy. While P2X₇R activation can induce inflammatory signalling pathways, particularly in microglia, we focus here specifically on the contributions of astrocytic P2X₇R to synaptic changes and protein aggregate clearance in AD, highlighting cell-specific roles of this purinoceptor activation that could be targeted to slow disease progression.