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Published on: December 26, 2016
Microglial purinergic signaling in Alzheimer's disease
Shu-Ya Mei1, Ning Zhang1, Meng-Jing Wang1
1School of Acupuncture and Tuina, Shaanxi University of Traditional Chinese Medicine, No. 1 Middle Section of Shi-Ji Avenue, Xianyang, Shaanxi, 712046, People's Republic of China.
Abstract:
Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease. The prevalent features of AD pathogenesis are the appearance of β-amyloid (Aβ) plaques and neurofibrillary tangles, which cause microglial activation, synaptic deficiency, and neuronal loss. Microglia accompanies AD pathological processes and is also linked to cognitive deficits. Purinergic signaling has been shown to play a complex and tight interplay with the chemotaxis, phagocytosis, and production of pro-inflammatory factors in microglia, which is an important mechanism for regulating microglia activation. Here, we review recent evidence for interactions between AD, microglia, and purinergic signaling and find that the purinergic P2 receptors pertinently expressed on microglia are the ionotropic receptors P2X4 and P2X7, and the subtypes of P2YRs expressed by microglia are metabotropic receptors P2Y2, P2Y6, P2Y12, and P2Y13. The adenosine P1 receptors expressed in microglia include A1R, A2AR, and A2BR. Among them, the activation of P2X4, P2X7, and adenosine A1, A2A receptors expressed in microglia can aggravate the pathological process of AD, whereas P2Y2, P2Y6, P2Y12, and P2Y13 receptors expressed by microglia can induce neuroprotective effects. However, A1R activation also has a strong neuroprotective effect and has a significant anti-inflammatory effect in chronic neuroinflammation. These receptors regulate a variety of pathophysiological processes in AD, including APP processing, Aβ production, tau phosphorylation, neuroinflammation, synaptic dysfunction, and mitochondrial dysfunction. This review also provides key pharmacological advances in purinergic signaling receptors.
Insights
Purinergic signaling in Alzheimer's disease (AD) involves microglia. Specific P2 and adenosine receptors can worsen or protect against AD pathology, offering therapeutic targets.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid plaques and neurofibrillary tangles.
- Microglia, the brain's immune cells, are central to AD pathogenesis, influencing inflammation and neuronal function.
- Purinergic signaling, involving P2 and adenosine receptors, critically modulates microglial activity in AD.
Purpose of the Study:
- To review the complex interactions between Alzheimer's disease, microglial function, and purinergic signaling pathways.
- To identify specific purinergic receptors on microglia that influence AD progression.
- To highlight potential pharmacological targets within the purinergic system for AD treatment.
Main Methods:
- Comprehensive literature review of studies investigating purinergic signaling in Alzheimer's disease.
- Analysis of microglial purinergic receptor expression (P2X, P2Y, Adenosine A1/A2) in the context of AD.
- Synthesis of evidence on how these receptors modulate AD-related pathophysiological processes.
Main Results:
- Microglia express ionotropic P2X4/P2X7 and metabotropic P2Y2/P2Y6/P2Y12/P2Y13 receptors, as well as adenosine A1/A2A/A2B receptors.
- Activation of P2X4, P2X7, and adenosine A1/A2A receptors exacerbates AD pathology.
- Activation of P2Y2, P2Y6, P2Y12, P2Y13, and adenosine A1 receptors demonstrates neuroprotective and anti-inflammatory effects in AD.
Conclusions:
- Purinergic signaling pathways play a dual role in Alzheimer's disease, with specific receptors mediating detrimental or beneficial effects.
- Targeting microglial purinergic receptors offers a promising therapeutic strategy for modulating AD pathogenesis.
- Further research into these receptors could lead to novel pharmacological interventions for Alzheimer's disease.
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