Journal
JOURNAL OF NEUROSCIENCE
Volume 35, Issue 38, Pages 12986-12993Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.5241-14.2015
Keywords
Alzheimer's disease; ATF4; cognitive enhancer; memory consolidation; translation regulation
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Funding
- European Union [HEALTH-F2-2009-241498]
- German-Israeli Foundation DIP [RO3971/1-1]
- Morasha (Israeli Science Foundation Legacy Heritage) [1315/09]
- Wolfson charitable trust
- Ministry of Science and Technology Eshkol Fellowship
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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 alpha. In the present study, we tested the possible involvement of additional members of the eIF2 alpha pathway and identified increased mRNA expression of negative transcription factor ATF4 (aka CREB2) both in human and a mouse 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.
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