Moradi Fatemeh, Mokhtari Tahmineh
Department of Cell Biology and Neuroscience, Rowan University School of Osteopathic Medicine, Stratford, New Jersey, USA.
Department of Histology and Embryology, Faculty of Basic Medical Sciences, Hubei University of Medicine, Shiyan, People's Republic of China.
J Biochem Mol Toxicol. 2025 Feb;39(2):e70071. doi: 10.1002/jbt.70071.
The coexistence of Alzheimer's disease (AD) and chronic pain (CP) in the elderly population has been extensively documented, and a growing body of evidence supports the potential interconnections between these two conditions. This comprehensive review explores the mechanisms by which CP may contribute to the development and progression of AD, with a particular focus on neuroinflammatory pathways and the role of microglia, as well as the activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome. The review proposes that prolonged pain processing in critical brain regions can dysregulate the activity of the NLRP3 inflammasome within microglia, leading to the overproduction of pro-inflammatory cytokines and excessive oxidative stress in these regions. This aberrant microglial response also results in localized neuroinflammation in brain areas crucial for cognitive function. Additionally, CP as a persistent physiological and psychological stressor may be associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction, systemic inflammation, disruption of the blood-brain barrier (BBB), and neuroinflammation. These pathophysiological changes can cause morphological and functional impairments in brain regions responsible for cognition, memory, and neurotransmitter production, potentially contributing to the development and progression of CP-associated AD. Resultant neuroinflammation can further promote amyloid-beta (Aβ) plaque deposition, a hallmark of AD pathology. Potential therapeutic interventions targeting these neuroinflammatory pathways, particularly through the regulation of microglial NLRP3 activation, hold promise for improving outcomes in individuals with comorbid CP and AD. However, further research is required to fully elucidate the complex interplay between these conditions and develop effective treatment strategies.
老年人群中阿尔茨海默病（AD）与慢性疼痛（CP）并存的情况已有大量记载，越来越多的证据支持这两种病症之间存在潜在的相互联系。本综述全面探讨了CP可能促使AD发生和发展的机制，特别关注神经炎症途径、小胶质细胞的作用以及含3个吡啉结构域的NLR家族（NLRP3）炎性小体的激活。该综述提出，关键脑区长期的疼痛处理会使小胶质细胞内NLRP3炎性小体的活性失调，导致这些区域促炎细胞因子过度产生和氧化应激过度。这种异常的小胶质细胞反应还会在对认知功能至关重要的脑区引发局部神经炎症。此外，CP作为一种持续的生理和心理应激源，可能与下丘脑 - 垂体 - 肾上腺（HPA）轴功能障碍、全身炎症、血脑屏障（BBB）破坏以及神经炎症有关。这些病理生理变化会导致负责认知、记忆和神经递质产生的脑区出现形态和功能损伤，可能促使与CP相关的AD的发生和发展。由此产生的神经炎症会进一步促进淀粉样β（Aβ）斑块沉积，这是AD病理的一个标志。针对这些神经炎症途径的潜在治疗干预措施，特别是通过调节小胶质细胞NLRP3的激活，有望改善CP和AD共病个体的预后。然而，需要进一步研究以充分阐明这些病症之间的复杂相互作用并制定有效的治疗策略。
