中国神经再生研究(英文版) ›› 2025, Vol. 20 ›› Issue (7): 1981-1988.doi: 10.4103/NRR.NRR-D-24-00398

• 综述:退行性病与再生 • 上一篇    下一篇

缺血性卒中和晚发性阿尔茨海默病中的急性和慢性兴奋毒性

  

  • 出版日期:2025-07-15 发布日期:2024-11-26

Acute and chronic excitotoxicity in ischemic stroke and late-onset Alzheimer’s disease

Shan Ping Yu1, 2, *, Emily Choi1 , Michael Q. Jiang1, 2, Ling Wei1   

  1. 1 Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, USA;  2 Center for Visual and Neurocognitive Rehabilitation, Atlanta Veterans Affairs Medical Center, Decatur, GA, USA
  • Online:2025-07-15 Published:2024-11-26
  • Contact: Shan Ping Yu, MD, PhD, spyu@emory.edu.
  • Supported by:
    This work was supported by National Health Institute (NIH) grant NS099596 (to LW and SPY), NS114221 (to LW and SPY), Veterans Affair (VA) SPiRE grant RX003865 (to SPY). This work was also supported by the O. Wayne Rollins Endowment Fund (to SPY) and John E. Steinhaus Endowment Fund (to LW).

摘要: https://orcid.org/0000-0003-1335-1398 (Shan Ping Yu)

Abstract: Stroke and Alzheimer’s disease are common neurological disorders and often occur in the same individuals. The comorbidity of the two neurological disorders represents a grave health threat to older populations. This review presents a brief background of the development of novel concepts and their clinical potentials. The activity of glutamatergic N-methyl-D-aspartate receptors and N-methyl-D-aspartate receptor-mediated Ca2+ influx is critical for neuronal function. An ischemic insult induces prompt and excessive glutamate release and drastic increases of intracellular Ca2+ mainly via N-methyl-Daspartate receptors, particularly of those at the extrasynaptic site. This Ca2+-evoked neuronal cell death in the ischemic core is dominated by necrosis within a few hours and days known as acute excitotoxicity. Furthermore, mild but sustained Ca2+ increases under neurodegenerative conditions such as in the distant penumbra of the ischemic brain and early stages of Alzheimer’s disease are not immediately toxic, but gradually set off deteriorating Ca2+-dependent signals and neuronal cell loss mostly because of activation of programmed cell death pathways. Based on the Ca2+ hypothesis of Alzheimer’s disease and recent advances, this Ca2+-activated “silent” degenerative excitotoxicity evolves from years to decades and is recognized as a unique slow and chronic neuropathogenesis. The N-methyl-D-aspartate receptor subunit GluN3A, primarily at the extrasynaptic site, serves as a gatekeeper for the N-methyl-D-aspartate receptor activity and is neuroprotective against both acute and chronic excitotoxicity. Ischemic stroke and Alzheimer’s disease, therefore, share an N-methyl-D-aspartate receptor- and Ca2+-mediated mechanism, although with much different time courses. It is thus proposed that early interventions to control Ca2+ homeostasis at the preclinical stage are pivotal for individuals who are susceptible to sporadic late-onset Alzheimer’s disease and Alzheimer’s disease-related dementia. This early treatment simultaneously serves as a preconditioning therapy against ischemic stroke that often attacks the same individuals during abnormal aging.

Key words: Ca2+ hypothesis, cognitive deficits, hyperactivity, late-onset Alzheimer’s disease, neurodegeneration, N-methyl-D-aspartate receptors, N-methyl-D-aspartate receptor subunits, pathogenesis, preventive treatment