神经元钙信号系统异常与阿尔茨海默病的“钙假说”

Neuronal Calcium Signaling System and“Calcium Hypothesis”of Alzheimer’s Disease

钙信号是细胞调节各项生命活动的重要机制。神经元通过胞外钙离子(calcium ion,Ca^(2+))内流、内质网Ca;释放以及Ca;释放介导的Ca;内流等方式产生具有时空特异性的钙信号,用于调控多种生物学过程,例如动作电位的调节、神经递质的释放、轴突的生长以及突触可塑性等。神经元胞内Ca;浓度因受到细胞精确调控而处于动态平衡之中。若钙信号失调导致平衡被打破,则会造成神经元功能异常甚至死亡。近年来多项研究表明,钙稳态失衡与神经退行性疾病,例如阿尔茨海默病等的产生和发展密切相关,由此发展出关于阿尔茨海默病的钙假说。该假说认为,神经元钙稳态调节机制的持续性改变是神经元功能失常、大脑产生慢性疾病的重要因素。阿尔茨海默病发生发展过程中,神经元胞浆钙水平异常增高,致使多种钙依赖性酶的活性异常,进而影响基因转录。虽然内质网钙稳态的变化目前仍存在一定的争议,但较为确定的是线粒体中存在着钙超载的现象,导致氧化磷酸化反应下调,活性氧的产量增加,进而引发细胞凋亡。本文主要介绍了神经元钙信号系统及其功能,简要梳理了阿尔茨海默病钙假说的相关研究,并对后续研究进行了展望。

Calcium(Ca;)signaling plays critical roles in controlling numerous cellular processes.It is generated by either Ca^(2+) influxes from extracellular spaces or releases from endoplasmic reticulum.Neuronal Ca^(2+) signaling regulates a variety of physiological processes including excitability,neurotransmitter release,axon growth and synaptic plasticity.Neurons require extremely precise spatio-temporal control of Ca^(2+) concentration to maintain a proper Ca^(2+) homeostasis.Altered Ca^(2+) signals might account for the disruption of this homeostasis,and may cause neuronal pathological changes,even lead to cell death.Recent evidences indicate that Ca^(2+) dyshomeostasis are closely interrelated with neurodegenerative disorders,such as Alzheimer’s disease(AD),leading to the formulation of the calcium hypothesis of AD.The hypothesis states that sustained changes in molecular mechanism that regulate cellular Ca^(2+) homeostasis could play a critical role in many of the neural dysfunctions underlying chronic brain disorders.In the pathogenesis of AD,the elevated cytosolic Ca^(2+) levels influence the activity of cellular enzymes and transcription of downstream genes.It is controversial whether the ER Ca^(2+) content is altered in AD or not.It is well established that there exists mitochondrial Ca^(2+) overload in AD,which leads to reduced energy metabolism,increased levels of reactive oxygen species and apoptosis.Aiming to provide some inspiration for future research,we here briefly described neuronal Ca^(2+) signaling system,reviewed recent progresses regarding the Ca^(2+) hypothesis of Alzheimer’s disease.