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<p>Alzheimer’s disease (AD) is a&#xa0;gradually worsening neurodegenerative disorder marked by memory impairment, poor judgment, difficulty completing tasks, changes in Behaviour, hallucinations, and delusions. The underlying mechanism of AD featured extracellular aggregation of the Aβ plaques, intracellular deposition of tau protein, accumulation of neurofibrillary tangles (NFTs), and synaptic dysfunction. In the central nervous system (CNS), purines, namely adenosine triphosphate (ATP) and its metabolites like adenosine diphosphate (ADP), adenosine monophosphate (AMP), and adenosine, function extracellularly. The P2X7 receptor (P2X7R) is a&#xa0;trimeric, ion-gated channel regulated by ATP, found in neurons, astrocytes, oligodendrocytes, and microglia. Several <i>in-vivo</i> and <i>in-vitro</i> studies have implied the importance of P2X7R in the brain pathology of AD. In AD, activation of P2X7R results in mechanisms contributing to its pathophysiology, such as neuroinflammation, accumulation of amyloid‑β, amyloid precursor protein processing (APP), oxidative stress, and synaptic dysfunction. Furthermore, this process leads to the production and release of chemokines and triggers the inflammasome pathway, particularly NLRP3, which modulates the inflammatory response and manages amyloid‑β accumulation by controlling both the NLRP3 inflammasome pathway and the expression of several chemokines. Thus, pharmacological inhibition or knockdown of P2X7R leads to improvement in symptoms of various AD mouse models. This review focuses on the functions and role of P2X7R in the mechanisms of AD pathophysiology, including neuroinflammation, oxidative stress, accumulation of amyloid‑β, synaptic dysfunction, and APP processing, and acts as an emerging target in AD.</p>

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Unlocking the P2X7 Pathway: A Therapeutic Target in Alzheimer’s Disease

  • 期刊论文

  • 发表日期：

    2024年12月1日

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  • Sanjeevan Gupta,
  • Khadga Raj Aran

摘要

Alzheimer’s disease (AD) is a gradually worsening neurodegenerative disorder marked by memory impairment, poor judgment, difficulty completing tasks, changes in Behaviour, hallucinations, and delusions. The underlying mechanism of AD featured extracellular aggregation of the Aβ plaques, intracellular deposition of tau protein, accumulation of neurofibrillary tangles (NFTs), and synaptic dysfunction. In the central nervous system (CNS), purines, namely adenosine triphosphate (ATP) and its metabolites like adenosine diphosphate (ADP), adenosine monophosphate (AMP), and adenosine, function extracellularly. The P2X7 receptor (P2X7R) is a trimeric, ion-gated channel regulated by ATP, found in neurons, astrocytes, oligodendrocytes, and microglia. Several in-vivo and in-vitro studies have implied the importance of P2X7R in the brain pathology of AD. In AD, activation of P2X7R results in mechanisms contributing to its pathophysiology, such as neuroinflammation, accumulation of amyloid‑β, amyloid precursor protein processing (APP), oxidative stress, and synaptic dysfunction. Furthermore, this process leads to the production and release of chemokines and triggers the inflammasome pathway, particularly NLRP3, which modulates the inflammatory response and manages amyloid‑β accumulation by controlling both the NLRP3 inflammasome pathway and the expression of several chemokines. Thus, pharmacological inhibition or knockdown of P2X7R leads to improvement in symptoms of various AD mouse models. This review focuses on the functions and role of P2X7R in the mechanisms of AD pathophysiology, including neuroinflammation, oxidative stress, accumulation of amyloid‑β, synaptic dysfunction, and APP processing, and acts as an emerging target in AD.