Abstract
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and the principal cause of dementia. The main neuropathological features of AD include amyloid β (Aβ) accumulations in senile plaques, aggregated and phosphorylated tau deposits in neurofibrillary tangles, and an extensive loss of neurons and synapses. These hallmarks are accompanied by a complex glial reactivity and chronic neuroinflammation primarily driven by microglia and astrocytes, which has emerged as a key contributor to the onset and progression of AD.The purinergic receptor P2X7 (P2X7R) is an ionotropic receptor that responds to high concentrations of ATP, typically released by damaged or activated cells, and is best known for its role as regulator of inflammatory responses in the immune system. While the localisation and functions of P2X7R in the CNS remain incompletely understood, emerging evidence associates this purinoreceptor with a wide spectrum of neurological diseases in which neuroinflammation contributes to the disease process, including AD. P2X7R inhibition in AD models is linked to a reduction of pathological hallmarks, including Aβ burden and tau modifications, and ameliorates cognitive deficits in vivo. This thesis aims to better understand the cell-type specific contribution of P2X7R to neuroinflammatory signalling in relation to Aβ and tau pathology in AD and ultimately, to shed light on the therapeutic potential of P2X7R antagonism.
Changes in P2X7R expression and localisation relative to disease hallmarks and local inflammatory features were investigated in prefrontal and temporal cortex from post- mortem AD and unaffected control brain at different Braak stages. P2X7R was elevated in AD relative to control brain and showed regional differences in the upregulation pattern, in association with the accumulation of phosphorylated tau and Aβ at synapses and loss of post-synaptic markers. P2X7R was found to localise to human microglia as well as astrocytes in the vicinity of Aβ deposits in AD brain. This was accompanied by an upregulation of inflammatory cytokines such as IL-1β, CCL2 and CXCL1.
| Date of Award | 1 Nov 2022 |
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| Original language | English |
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| Supervisor | Wendy Noble (Supervisor) & Beatriz Gomez Perez-Nievas (Supervisor) |