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

Abstract

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.

Hippocampal purinergic P2X7 receptor level is increased in Alzheimer’s disease patients, and associated with amyloid and tau pathologies

“…Purinergic signalling mediated by purinergic receptors, particularly P2X7Rs, plays important roles in chronic immune and inflammatory responses (5, 18, 56). P2X7R is an adenosine triphosphate (ATP)-gated ion channel expressed on astrocytes (5), microglia and oligodendrocytes in the brain and macrophages in the periphery.…”

“…Purinergic signalling mediated by purinergic receptors, particularly P2X7Rs, plays important roles in chronic immune and inflammatory responses (5, 18, 56). P2X7R is an adenosine triphosphate (ATP)-gated ion channel expressed on astrocytes (5), microglia and oligodendrocytes in the brain and macrophages in the periphery. P2X7R is expressed at low levels under physiological conditions when the extracellular ATP concentration is below the threshold required for activation, while it is activated when ATP levels rise above the threshold under pathological conditions.…”

Increased regional P2X7R uptake detected by [18F]GSK1482160 PET in a tauopathy mouse model

“…Purinergic signalling occurs in individuals with cognitive disturbances (22), cognitive impairment and neuropsychiatric symptoms of AD (51). Purinergic receptors, particularly P2X7Rs, play important roles in chronic immune and inflammatory responses (2, 11). In the central nervous system, P2X7R is expressed on microglia, astrocytes (2) and oligodendrocytes, but its expression on neurons is still unclear (11).…”

“…Purinergic receptors, particularly P2X7Rs, play important roles in chronic immune and inflammatory responses (2, 11). In the central nervous system, P2X7R is expressed on microglia, astrocytes (2) and oligodendrocytes, but its expression on neurons is still unclear (11). P2X7R has proinflammatory functions by increasing the level of adenosine triphosphate, which activates P2X7R and leads to proinflammatory cytokines.…”

“…In addition, P2X7R affects Aβ production by influencing alpha-secretase-dependent amyloid precursor protein (APP) processing (9, 41) and increasing plaque formation mediated by glycogen synthase kinase-3β (12). P2X7R also influences the aggregate burden of tau in human tauopathies and results in distinct signalling in microglia and astrocytes (1, 2).…”