Therapeutic implications of purinergic receptor P2X4 in ischemic stroke

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Abstract/Summary Cerebrovascular diseases including ischemic stroke contribute to Alzheimer disease (AD) neuropathological changes, including brain atrophy and accumulation of abnormal proteins such as amyloid beta (Aβ). In the geriatric population, the incidence of dementia significantly increases after stroke. Nevertheless, the molecular links between stroke and dementia are not clearly understood but could be related to neuroinflammation. Neuroinflammation plays a key role in the pathogenesis of AD, the most prevalent form of dementia. Among the innate immune cells, brain resident microglia and infiltrated monocytes –– collectively called brain macrophages –– are the primary players in neuroinflammation. Activated brain macrophages exhibit diverse phenotypes and complex interactions during AD pathology. P2X4R, the most calcium-permeable and robust P2XR subtype present on brain macrophages, is activated by extracellular ATP. Acute activation of P2X4R on macrophages leads to inflammasome formation and thus may contribute to progressive neuroinflammation during AD progression. We previously showed that P2X4R expression and activity in myeloid cells increases swiftly and exacerbates injury after ischemic stroke. Either pharmacological inhibition or genetic deletion of P2X4R showed acute neuroprotective effects after stroke in young adult mice. P2X4R blockade reduces microglial activation and CNS infiltration of peripheral monocytes after stroke. Infiltrated monocytes from P2X4R KO mice show increased clearance of dead tissue after stroke. These data support the hypothesis that P2X4R activation of both circulating monocytes and microglia exacerbate neuroinflammation and inhibit post- stroke recovery. We will use our mouse model of myeloid cell-specific P2X4R deficiency in conjunction with 3xTG AD model to evaluate P2X4R and/or its downstream targets for the treatment of AD and AD-related dementia. In the following two aims, we want to know: 1) If P2X4R expression increases in the 3xTG AD mouse model and if its absence reduces brain damage; and 2) If deletion of P2X4R on myeloid cells improves the cognitive deficiencies that occur in AD mice with or without stroke. Regardless of the results, these simple aims will be able to identify if P2X4R plays a role in AD progression.