title: PKR Inhibition Rescues Memory Deficit and ATF4 Overexpression in ApoE ε4 Human Replacement Mice.
abstract: 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 eIF2α. In the present study, we tested the possible involvement of additional members of the eIF2α 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. Significance statement: ATF4 mRNA relative quantities are elevated in ApoE4 allele carriers compared with noncarrier controls. This is true also for the ApoE ε4 human replacement mice. ApoE4 mice injected with PKR inhibitor (PKRi) demonstrate a significant reduction in ATF4 expression levels 3 h after one injection of PKRi. Treatment of ApoE4 human replacement mice with the PKRi before learning rescues the memory impairment of the ApoE4 AD model mice. We think that these results propose a new mechanism by which ApoE4 affects brain function and suggest that inhibition of PKR is a way to restore memory impairment in early stages of sporadic AD.
authors.affiliation: Sagol Department of Neurobiology and.
authors.forename: Yifat
authors.initials: Y
authors.lastname: Segev
authors.affiliation: Sagol Department of Neurobiology and.
authors.forename: Iliana
authors.initials: I
authors.lastname: Barrera
authors.affiliation: Sagol Department of Neurobiology and.
authors.forename: Hadile
authors.initials: H
authors.lastname: Ounallah-Saad
authors.affiliation: Department of Biomedicine and KG Jebsen Centre for Research on Neuropsyhiatric Disorders, University of Bergen, N-5009 Bergen, Norway.
authors.forename: Karin
authors.initials: K
authors.lastname: Wibrand
authors.affiliation: Department of Biomedicine and KG Jebsen Centre for Research on Neuropsyhiatric Disorders, University of Bergen, N-5009 Bergen, Norway.
authors.forename: Ida
authors.initials: I
authors.lastname: Sporild
authors.affiliation: Sagol Department of Neurobiology and.
authors.forename: Adva
authors.initials: A
authors.lastname: Livne
authors.affiliation: Sagol Department of Neurobiology and.
authors.forename: Tali
authors.initials: T
authors.lastname: Rosenberg
authors.affiliation: Sagol Department of Neurobiology and.
authors.forename: Orit
authors.initials: O
authors.lastname: David
authors.affiliation: Sagol Department of Neurobiology and.
authors.forename: Meshi
authors.initials: M
authors.lastname: Mints
authors.affiliation: Department of Biomedicine and KG Jebsen Centre for Research on Neuropsyhiatric Disorders, University of Bergen, N-5009 Bergen, Norway.
authors.forename: Clive R
authors.identifier: http://orcid.org/0000-0001-5958-7115
authors.initials: CR
authors.lastname: Bramham
authors.affiliation: Sagol Department of Neurobiology and Center for Gene Manipulation in the Brain, University of Haifa, Haifa 3498838, Israel, and kobir@psy.haifa.ac.il.
authors.forename: Kobi
authors.initials: K
authors.lastname: Rosenblum
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000818:Animals; D053318:Apolipoprotein E3 / Q000235:genetics; D053327:Apolipoprotein E4 / Q000235:genetics*; D003213:Conditioning, Psychological / Q000502:physiology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005239:Fear / Q000523:psychology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011494:Protein Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D018709:Statistics, Nonparametric
chemical_list: D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; C081452:Atf4 protein, mouse; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D051701:Activating Transcription Factor 4; D011494:Protein Kinases
keywords: ATF4; Alzheimer's disease; cognitive enhancer; memory consolidation; translation regulation