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Limited effects of an eIF2?S51A 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 2? (eIF2?) at serine 51. Increased phosphorylation of eIF2? alters translational control and may thereby have adverse effects on synaptic plasticity, learning, and memory. To analyze if increased levels of p-eIF2? indeed promote AD-related neurocognitive impairments, we crossed 5xFAD transgenic mice with an eIF2?(S51A) knock-in line that expresses the nonphosphorylatable eIF2? variant eIF2?(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 eIF2?(S51A) allele. Telemetric intracranial EEG recordings revealed no measurable effects of the eIF2?(S51A) allele on 5xFAD-associated epileptic activity. Microarray-based transcriptome analyses showed clear transcriptional alterations in 5xFAD hippocampus that were not corrected by the eIF2?(S51A) allele. In contrast to prior studies, our immunoblot analyses did not reveal increased levels of p-eIF2? in the hippocampus of 5xFAD mice, suggesting that elevated p-eIF2? levels are not a universal feature of AD models. Collectively, our data indicate that 5xFAD-related pathologies do not necessarily require hyperphosphorylation of eIF2? to emerge; they also show that heterozygosity for the nonphosphorylatable eIF2?(S51A) allele has limited effects on 5xFAD-related disease manifestations.

SUBMITTER: Paesler K

PROVIDER: S-EPMC4391319 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Limited effects of an eIF2αS51A allele on neurological impairments in the 5xFAD mouse model of Alzheimer's disease.

Paesler Katharina K Xie Kan K Hettich Moritz M MM Siwek Magdalena E ME Ryan Devon P DP Schröder Susanne S Papazoglou Anna A Broich Karl K Müller Ralf R Trog Astrid A Garthe Alexander A Kempermann Gerd G Weiergräber Marco M Ehninger Dan D

Neural plasticity 20150326

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 ...[more]

PMID: 25883808

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Project description:There is an urgent need to improve the translational validity of Alzheimer's disease (AD) mouse models. Introducing genetic background diversity in AD mouse models has been proposed as a way to increase validity and enable the discovery of previously uncharacterized genetic contributions to AD susceptibility or resilience. However, the extent to which genetic background influences the mouse brain proteome and its perturbation in AD mouse models is unknown. In this study, we crossed the 5XFAD AD mouse model on a C57BL/6J (B6) inbred background with the DBA/2J (D2) inbred background and analyzed the effects of genetic background variation on the brain proteome in F1 progeny. Both genetic background and 5XFAD transgene insertion strongly affected protein variance in the hippocampus and cortex (n = 3,368 proteins). Protein co-expression network analysis identified 16 modules of highly co-expressed proteins common across the hippocampus and cortex in 5XFAD and non-transgenic mice. Among the modules strongly influenced by genetic background were those related to small molecule metabolism and ion transport. Modules strongly influenced by the 5XFAD transgene were related to lysosome/stress responses and neuronal synapse/signaling. The modules with the strongest relationship to human disease-neuronal synapse/signaling and lysosome/stress response-were not significantly influenced by genetic background. However, other modules in 5XFAD that were related to human disease, such as GABA synaptic signaling and mitochondrial membrane modules, were influenced by genetic background. Most disease-related modules were more strongly correlated with AD genotype in the hippocampus compared with the cortex. Our findings suggest that the genetic diversity introduced by crossing B6 and D2 inbred backgrounds influences proteomic changes related to disease in the 5XFAD model, and that proteomic analysis of other genetic backgrounds in transgenic and knock-in AD mouse models is warranted to capture the full range of molecular heterogeneity in genetically diverse models of AD.

Dataset Information

Limited effects of an eIF2?S51A allele on neurological impairments in the 5xFAD mouse model of Alzheimer's disease.

Publications

Limited effects of an eIF2αS51A allele on neurological impairments in the 5xFAD mouse model of Alzheimer's disease.

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