PKR inhibition rescues memory deficit and atf4 overexpression in apoe ε4 human replacement mice

Yifat Segev, Iliana Barrera, Hadile Ounallah-Saad, Karin Wibrand, Ida Sporild, Adva Livne, Tali Rosenberg, Orit David, Meshi Mints, Clive R. Bramham, Kobi Rosenblum

Research output: Contribution to journalArticlepeer-review


Sporadic Alzheimer’s disease (AD) is an incurable neurodegenerative disease with clear pathological hallmarks, brain dysfunction, and unknown etiology. Here, we tested the hypothesis that there is a link between genetic risk factors for AD, cellular metabolic stress, and transcription/translation regulation. In addition, we aimed at reversing the memory impairment observed in a mouse model of sporadic AD. We have previously demonstrated that the most prevalent genetic risk factor for AD, the ApoE4 allele, is correlated with increased phosphorylation of the translation factor eIF2 α In the present study, we tested the possible involvement of additional members of the eIF2α pathway and identified increasedmRNAexpression of negative transcription factorATF4 (aka CREB2) both inhumanand amouse model expressing the human ApoE4 allele. Furthermore, injection of a PKR inhibitor rescued memory impairment and attenuated ATF4 mRNA increased expression in the ApoE4 mice. The results propose a new mechanism by which ApoE4 affects brain function and further suggest that inhibition of PKR is a way to restore ATF4 overexpression and memory impairment in early stages of sporadic AD.

Original languageEnglish
Pages (from-to)12986-12993
Number of pages8
JournalJournal of Neuroscience
Issue number38
StatePublished - 23 Sep 2015

Bibliographical note

Publisher Copyright:
© 2015 the authors.


  • ATF4
  • Alzheimer’s disease
  • Cognitive enhancer
  • Memory consolidation
  • Translation regulation

ASJC Scopus subject areas

  • General Neuroscience


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