Essays in Biochemistry · 6 authors, 5 centres
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This review examines how astrocytes, key homeostatic cells in the brain, undergo heterogeneous changes in Alzheimer's disease (AD), including reactive remodeling and loss of function. It focuses on the purinergic receptor P2X7R, whose expression is increased in AD and whose activation in astrocytes may contribute to synaptic dysfunction and impaired protein clearance. The authors suggest that targeting astrocytic P2X7R could offer a novel therapeutic strategy to slow AD progression.
**Background:** Alzheimer's disease (AD) is characterized by progressive deposition of amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs), along with glial alterations, synapse loss, and cognitive decline. Astrocytes, which constitute 20–40% of glial cells in humans, perform critical homeostatic functions including synaptic regulation, ion homeostasis, blood–brain barrier maintenance, and clearance of protein aggregates. In AD, astrocytes undergo heterogeneous morphological, molecular, and functional changes—termed astrocytic reactivity—which include both reactive remodeling and loss of homeostatic functions. The purinergic receptor P2X7R, activated by high concentrations of ATP, is upregulated in AD brain and has been implicated in neuroinflammation and synaptic dysfunction. This review focuses specifically on the contributions of astrocytic P2X7R to synaptic changes and protein aggregate clearance in AD.
**Methods:** This is a narrative review that synthesizes evidence from human postmortem studies, animal models (including APP/PS1, Tg2576, J20, 5xFAD, and tauopathy mice), and in vitro experiments. The authors discuss molecular, electrophysiological, and behavioral data on P2X7R expression, activation, and antagonism in the context of astrocyte function in AD.
**Key Results:** P2X7R mRNA and protein levels are increased in AD postmortem brain compared to non-demented controls, and this increase is recapitulated in transgenic mouse models of amyloidosis (e.g., Tg2576, APP/PS1, J20) and tauopathy. P2X7R upregulation is particularly prominent around Aβ plaques. Pharmacological antagonism or genetic deletion of P2X7R improves cognitive and synaptic impairments in mouse models of amyloidosis and tauopathy. For example, genetic deletion of P2X7R in APP/PS1 mice improved long-term synaptic plasticity, spatial learning, and memory dysfunction relative to wild-type littermates. P2X7R antagonism in tauopathy models (e.g., mice carrying MAPT mutations G272V and/or P301S) ameliorates cognitive and behavioral deficits as well as synaptic dysfunction. In astrocytes, P2X7R activation induces Ca2+ influx, which can modulate glutamate release and potentially contribute to excitotoxicity. Astrocytes also internalize Aβ and tau aggregates, and P2X7R signaling may influence autophagy and protein clearance pathways, including through regulation of HSPB1 and HSPGs. However, direct evidence linking astrocytic P2X7R to protein clearance in AD is limited, and the authors call for further investigation.
**Clinical Implications:** The review highlights P2X7R as a potential therapeutic target in AD, given its upregulation in disease and the beneficial effects of its blockade in animal models. However, the cell-specific roles of P2X7R—particularly in astrocytes versus microglia—need to be clarified to develop targeted interventions that avoid off-target effects. Understanding how astrocytic P2X7R contributes to synaptic dysfunction and protein clearance could lead to novel strategies to slow AD progression.