Dejakaisaya Hattapark, Kwan Patrick, Jones Nigel C
Department of Neuroscience, Central Clinical School, The Alfred Hospital, Monash University, Melbourne, Vic., Australia.
Faculty of Medicine and Public Health, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, Thailand.
Epilepsia. 2021 Jul;62(7):1485-1493. doi: 10.1111/epi.16918. Epub 2021 May 10.
Alzheimer's disease (AD) can increase the risk of epilepsy by up to 10-fold compared to healthy age-matched controls. However, the pathological mechanisms that underlie this increased risk are poorly understood. Because disruption in brain glutamate homeostasis has been implicated in both AD and epilepsy, this might play a mechanistic role in the pathogenesis of epilepsy in AD. Prior to the formation of amyloid beta (Aβ) plaques, the brain can undergo pathological changes as a result of increased production of amyloid precursor protein (APP) and Aβ oligomers. Impairments in the glutamate uptake ability of astrocytes due to astrogliosis are hypothesized to be an early event occurring before Aβ plaque formation. Astrogliosis may increase the susceptibility to epileptogenesis of the brain via accumulation of extracellular glutamate and resulting excitotoxicity. Here we hypothesize that Aβ oligomers and proinflammatory cytokines can cause astrogliosis and accumulation of extracellular glutamate, which then contribute to the pathogenesis of epilepsy in AD. In this review article, we consider the evidence supporting a potential role of dysfunction of the glutamate-glutamine cycle and the astrocyte in the pathogenesis of epilepsy in AD.
与年龄匹配的健康对照组相比，阿尔茨海默病（AD）可使癫痫风险增加多达10倍。然而，这种风险增加背后的病理机制仍知之甚少。由于脑谷氨酸稳态破坏与AD和癫痫均有关联，这可能在AD癫痫发病机制中起作用。在淀粉样β（Aβ）斑块形成之前，由于淀粉样前体蛋白（APP）和Aβ寡聚体产生增加，大脑会发生病理变化。星形胶质细胞增生导致星形胶质细胞谷氨酸摄取能力受损被认为是Aβ斑块形成之前发生的早期事件。星形胶质细胞增生可能通过细胞外谷氨酸积累及由此产生的兴奋性毒性增加大脑对癫痫发生的易感性。在此，我们假设Aβ寡聚体和促炎细胞因子可导致星形胶质细胞增生和细胞外谷氨酸积累，进而促成AD癫痫的发病机制。在这篇综述文章中，我们考量了支持谷氨酸-谷氨酰胺循环功能障碍和星形胶质细胞在AD癫痫发病机制中潜在作用的证据。
