Environmental factors in the development and progression of late-onset Alzheimer's disease  

作　　者：Moses N. Wainaina Zhichun Chen Chunjiu Zhong 

机构地区：[1]Department of Neurology, Zhongshan Hospital [2]State Key Laboratory of Medical Neurobiology, Fudan University [3]Pwani University [4]Institutes of Brain Science [5]Fudan University

出　　处：《Neuroscience Bulletin》2014年第2期253-270,共18页神经科学通报（英文版）

基　　金：supported by National Basic Research Development Program(973 Program)of China(2011CBA00400);the National Natural Science Foundation of China(91332201);the Natural Science Foundation of Shanghai Municipality,China(13JC1401500);the Fund for Medical Emerging Cutting-edge Technology of Shanghai Municipality,China(SHDC12012114)

摘　　要：Late-onset Alzheimer＇s disease （LOAD） is an age-related neurodegenerative disorder characterized by gradual loss of synapses and neurons, but its pathogenesis remains to be clarified. Neurons live in an environment constituted by neurons themselves and glial cells. In this review, we propose that the neuronal degeneration in the AD brain is partially caused by diverse environmental factors. We first discuss various environmental stresses and the corresponding responses at different levels. Then we propose some mechanisms underlying the specific pathological changes, in particular, hypothalamic-pituitary adrenal axis dysfunction at the systemic level; cerebrovascular dysfunction, metal toxicity, glial activation, and Aβ toxicity at the intercellular level; and kinase-phosphatase imbalance and epigenetic modification at the intracellular level. Finally, we discuss the possibility of developing new strategies for the prevention and treatment of LOAD from the perspective of environmental stress. We conclude that environmental factors play a significant role in the development of LOAD through multiple pathological mechanisms.Late-onset Alzheimer＇s disease （LOAD） is an age-related neurodegenerative disorder characterized by gradual loss of synapses and neurons, but its pathogenesis remains to be clarified. Neurons live in an environment constituted by neurons themselves and glial cells. In this review, we propose that the neuronal degeneration in the AD brain is partially caused by diverse environmental factors. We first discuss various environmental stresses and the corresponding responses at different levels. Then we propose some mechanisms underlying the specific pathological changes, in particular, hypothalamic-pituitary adrenal axis dysfunction at the systemic level; cerebrovascular dysfunction, metal toxicity, glial activation, and Aβ toxicity at the intercellular level; and kinase-phosphatase imbalance and epigenetic modification at the intracellular level. Finally, we discuss the possibility of developing new strategies for the prevention and treatment of LOAD from the perspective of environmental stress. We conclude that environmental factors play a significant role in the development of LOAD through multiple pathological mechanisms.

关 键 词：Alzheimer＇s disease environmental factors corticotrophin-releasing factor CEREBROVASCULAR metatoxicity GLIA astrocyte microglia AI3 kinase PHOSPHATASE tau HYPERPHOSPHORYLATION epigenetic modificationDNA methylation histone acetylation 

分 类 号：R749.16[医药卫生—神经病学与精神病学]