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 2 alpha (eIF2 alpha) 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 alpha indeed promote AD-related neurocognitive impairments, we crossed 5xFAD transgenic mice with an eIF2 alpha(S51A) knock-in line that expresses the nonphosphorylatable eIF2 alpha variant eIF2 alpha(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 alpha(S51A) allele. Telemetric intracranial EEG recordings revealed no measurable effects of the eIF2 alpha(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 alpha(S51A) allele. In contrast to prior studies, our immunoblot analyses did not reveal increased levels of p-eIF2 alpha in the hippocampus of 5xFAD mice, suggesting that elevated p-eIF2 alpha levels are not a universal feature of AD models. Collectively, our data indicate that 5xFAD-related pathologies do not necessarily require hyperphosphorylation of eIF2 alpha to emerge; they also show that heterozygosity for the nonphosphorylatable eIF2 alpha(S51A) allele has limited effects on 5xFAD-related disease manifestations.