1Department of Neurology, Zhongshan Hospital; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China
2Institutes of Brain Science; Fudan University, Shanghai 200032, China
3Pwani University, Kilifi, Kenya

Abstract 

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.

Keywords

Alzheimer‘s disease; environmental factors; corticotrophin-releasing factor; cerebrovascular; metal toxicity; glia; astrocyte; microglia; Aβ; kinase; phosphatase; tau; hyperphosphorylation; epigenetic modi? cation; DNA methylation; histone acetylation

[SpringerLink]