Abstract
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease characterized by a progressive cognitive decline associated with global brain damage. Initially, intracellular paired helical filaments composed by hyperphosphorylated tau and extracellular deposits of amyloid-β (Aβ) were postulated as the causing factors of the synaptic dysfunction, neuroinflammation, oxidative stress, and neuronal death, detected in AD patients. Therefore, the vast majority of clinical trials were focused on targeting Aβ and tau directly, but no effective treatment has been reported so far. Consequently, only palliative treatments are currently available for AD patients. Over recent years, several studies have suggested the involvement of the purinergic receptor P2X7 (P2X7R), a plasma membrane ionotropic ATP-gated receptor, in the AD brain pathology. In this line, altered expression levels and function of P2X7R were found both in AD patients and AD mouse models. Consequently, genetic depletion or pharmacological inhibition of P2X7R ameliorated the hallmarks and symptoms of different AD mouse models. In this review, we provide an overview of the current knowledge about the role of the P2X7R in AD.
Highlights
Edited by: Luc Buee, Institut National de la Santé et de la Recherche Médicale (INSERM), France
- Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder. - P2X7R is upregulated in AD. - P2X7R is involved in microglial function, synaptopathy, oxidative stress, and amyloidogenic APP processing. - Induced pluripotent stem cell is a promising new therapeutic approach in AD
Due to the fact that many anti-amyloid clinical trials have failed, Aβ-directed therapies focusing on the reduction of parenchymal Aβ and amyloid deposits in AD brains have been put in doubt (Long and Holtzman, 2019)
Summary
There are only four commercial palliative-treatments available for symptomatic AD patients: three acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine) and memantine, a non-competitive NMDA receptors modulator (Long and Holtzman, 2019). Using in vitro and in vivo approaches, Martinez-Frailes et al (2019) have recently confirmed that ATP-induced P2X7R activation promotes microglial migration These findings might explain why there is an enrichment on P2X7R positive microglial cells around the senile plaques both in AD mouse models and in postmortem brain samples from AD patients (Parvathenani et al, 2003; McLarnon et al, 2006; Lee et al, 2011; MartinezFrailes et al, 2019). In human microglial cells, BzATP-induced P2X7R activation reduced its phagocytic capacity and produced mature caspase-1 by activating the inflammasome, revealing a close relationship between both events (Janks et al, 2018) Supporting this concept, the NLRP3 inflammasome inhibitor, MCC950, stimulates Aβ phagocytosis in vitro and reduces the number of senile hippocampal plaques in APP/PS1 mice, causing an improvement in their cognitive function (Dempsey et al, 2017). The loss of this capacity may contribute to the exacerbation of neuronal loss in the late stages of AD (Martinez-Frailes et al, 2019)
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