期刊
NEUROBIOLOGY OF AGING
卷 34, 期 3, 页码 863-872出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2012.06.020
关键词
Translation regulation; eIF2 alpha
资金
- ISF [1305/08]
- ISF-Morasha [1315/09]
Protein translation is regulated during both initiation and elongation phases to enable cells to accommodate for ever-changing environmental and internal states. Eukaryotic initiation factor-2 (eIF2)alpha, a major signaling pathway for responses to metabolic stress, controls translation initiation in various cells, including neurons, and affects cognitive functions. The main risk factor for sporadic Alzheimer's disease (SAD) is aging, and the main genetic risk factor reducing the age of SAD onset is the expression of apolipoprotein E (ApoE) 4. We tested the hypothesis that both genetic and aging risk factors converge on the eIF2 alpha pathway. Aged rodents showed increased eIF2 alpha phosphorylation in the brain, indicating a shift in the rate of translation initiation with increasing age. Interestingly, mice overexpressing human ApoE4 already, at an early age, exhibited increased eIF2 alpha phosphorylation together with mild impairment in cognitive tasks, compared with ApoE3 mice. These results suggest that the eIF2 alpha pathway is linked to SAD, possibly via genetic as well as prolonged metabolic stress, and these findings position it as a new and important target for treatment of the currently incurable Alzheimer's disease. (C) 2013 Elsevier Inc. All rights reserved.
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