title: Limited effects of an eIF2αS51A allele on neurological impairments in the 5xFAD mouse model of Alzheimer's disease.
abstract: Alzheimer's disease (AD) has been associated with increased phosphorylation of the translation initiation factor 2α (eIF2α) at serine 51. Increased phosphorylation of eIF2α alters translational control and may thereby have adverse effects on synaptic plasticity, learning, and memory. To analyze if increased levels of p-eIF2α indeed promote AD-related neurocognitive impairments, we crossed 5xFAD transgenic mice with an eIF2α(S51A) knock-in line that expresses the nonphosphorylatable eIF2α variant eIF2α(S51A). Behavioral assessment of the resulting mice revealed motor and cognitive deficits in 5xFAD mice that were, with the possible exception of locomotor hyperactivity, not restored by the eIF2α(S51A) allele. Telemetric intracranial EEG recordings revealed no measurable effects of the eIF2α(S51A) allele on 5xFAD-associated epileptic activity. Microarray-based transcriptome analyses showed clear transcriptional alterations in 5xFAD hippocampus that were not corrected by the eIF2α(S51A) allele. In contrast to prior studies, our immunoblot analyses did not reveal increased levels of p-eIF2α in the hippocampus of 5xFAD mice, suggesting that elevated p-eIF2α levels are not a universal feature of AD models. Collectively, our data indicate that 5xFAD-related pathologies do not necessarily require hyperphosphorylation of eIF2α to emerge; they also show that heterozygosity for the nonphosphorylatable eIF2α(S51A) allele has limited effects on 5xFAD-related disease manifestations.
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig Erhard Allee 2, 53175 Bonn, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Paesler
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig Erhard Allee 2, 53175 Bonn, Germany.
authors.forename: Kan
authors.initials: K
authors.lastname: Xie
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig Erhard Allee 2, 53175 Bonn, Germany.
authors.forename: Moritz M
authors.initials: MM
authors.lastname: Hettich
authors.affiliation: Federal Institute for Drugs and Medical Devices (BfArM), Kurt Georg Kiesinger Allee 3, 53175 Bonn, Germany.
authors.forename: Magdalena E
authors.initials: ME
authors.lastname: Siwek
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig Erhard Allee 2, 53175 Bonn, Germany.
authors.forename: Devon P
authors.initials: DP
authors.lastname: Ryan
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig Erhard Allee 2, 53175 Bonn, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schröder
authors.affiliation: Federal Institute for Drugs and Medical Devices (BfArM), Kurt Georg Kiesinger Allee 3, 53175 Bonn, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Papazoglou
authors.affiliation: Federal Institute for Drugs and Medical Devices (BfArM), Kurt Georg Kiesinger Allee 3, 53175 Bonn, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Broich
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Cologne, Kerpener Straße 62, 50937 Köln, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Müller
authors.affiliation: Institute of Molecular Psychiatry, University of Bonn, Sigmund Freud Straße 25, 53125 Bonn, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Trog
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Fetscherstraße 105, 01307 Dresden, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Garthe
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Fetscherstraße 105, 01307 Dresden, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Kempermann
authors.affiliation: Federal Institute for Drugs and Medical Devices (BfArM), Kurt Georg Kiesinger Allee 3, 53175 Bonn, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Weiergräber
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig Erhard Allee 2, 53175 Bonn, Germany.
authors.forename: Dan
authors.identifier: 0000-0001-7464-1335
authors.initials: D
authors.lastname: Ehninger
mesh_terms: D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D002540:Cerebral Cortex / Q000503:physiopathology; D004195:Disease Models, Animal; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D005239:Fear / Q000502:physiology; D055879:Gene Knock-In Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity; D010766:Phosphorylation; D053764:Presenilin-1 / Q000235:genetics; D012640:Seizures / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D015852:Eukaryotic Initiation Factor-2; C508853:PSEN1 protein, human; D053764:Presenilin-1