ApoE ε4 is associated with eIF2α phosphorylation and impaired learning in young mice

Yifat Segev, Daniel M. Michaelson, Kobi Rosenblum

Research output: Contribution to journalArticlepeer-review


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)α, 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 eIF2α pathway. Aged rodents showed increased eIF2α 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 eIF2α phosphorylation together with mild impairment in cognitive tasks, compared with ApoE3 mice. These results suggest that the eIF2α 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.

Original languageEnglish
Pages (from-to)863-872
Number of pages10
JournalNeurobiology of Aging
Issue number3
StatePublished - Mar 2013

Bibliographical note

Funding Information:
This work was supported by ISF ( 1305/08 ) and ISF-Morasha ( 1315/09 ) to K.R. The authors thank Dr. Alina Elkobi and Tali Rosenberg, M.Sc., for their technical assistance.


  • EIF2α
  • Translation regulation

ASJC Scopus subject areas

  • Clinical Neurology
  • Geriatrics and Gerontology
  • Aging
  • General Neuroscience
  • Developmental Biology


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