Limited Effects of an eIF2αS51A Allele on Neurological Impairments in the 5xFAD Mouse Model of Alzheimer’s Disease

Alzheimer’s disease (AD) has been associated with increased phosphorylation of the translation initiation factor 2α(eIF2α) at serine 51. Increased phosphorylation of eIF2αalters translational control and may thereby have adverse effects on synaptic plasticity, learning, and memory. To analyze if increased levels of p-eIF2αindeed promote AD-related neurocognitive impairments, we crossed 5xFAD transgenic mice with aneIF2αS51Aknock-in line that expresses the nonphosphorylatable eIF2αvarianteIF2αS51A. 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 theeIF2αS51Aallele. Telemetric intracranial EEG recordings revealed no measurable effects of theeIF2αS51Aallele on 5xFAD-associated epileptic activity. Microarray-based transcriptome analyses showed clear transcriptional alterations in 5xFAD hippocampus that were not corrected by theeIF2αS51Aallele. In contrast to prior studies, our immunoblot analyses did not reveal increased levels of p-eIF2αin the hippocampus of 5xFAD mice, suggesting that elevated p-eIF2αlevels are not a universal feature of AD models. Collectively, our data indicate that 5xFAD-related pathologies do not necessarily require hyperphosphorylation of eIF2αto emerge; they also show that heterozygosity for the nonphosphorylatableeIF2αS51Aallele has limited effects on 5xFAD-related disease manifestations.