Limited Effects of aneIF2α^S51AAllele 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.

Age‐related deterioration of motor function in male and female 5xFAD mice from 3 to 16 months of age

“…Therefore, we recommend use of these tests only in addition to other more sensitive and reliable measures of motor function (rotarod, balance beam). Although the reduced locomotor activity observed in 5xFAD mice between 12 and 15 months of age is consistent with some previous studies, other studies with 5xFAD mice at similar ages show hyperactivity in 5xFAD mice or no difference in locomotor activity . In addition, although some studies report decreased anxiety‐like behavior with increased time in the center of the OF, we did not detect this difference at any age tested, replicating several other studies .…”

Gender-Specific Hippocampal Dysrhythmia and Aberrant Hippocampal and Cortical Excitability in the APPswePS1dE9 Model of Alzheimer’s Disease

“…In age-matched transgenic and control mice it turned out that males exhibited significant higher body weight compared to females. However, different from other Alzheimer mouse models such as the 5XFAD [27, 28] no significant reduction of body weight in APPswePS1dE9 could be detected compared to controls in our study at 14 wks of age (control males 26.94 ± 0.64 g ( n = 10) versus transgenic males 26.16 ± 0.56 g ( n = 9), p = 0.3755; control females 21.23 ± 0.53 g ( n = 11) versus transgenic females 21.73 ± 0.35 g ( n = 11), p = 0.4416).…”

“…At the age of 6 months memory deficits in radial arm water maze are prominent [25] whereas, at 12 months, mice start exhibiting behavioral and cognitive deficits detectable in spatial navigation, reference learning, and Morris water maze. It has been hypothesized that seizure activity might account for sudden death in this line as intracerebral A β accumulation was suggested to be causally linked to epileptogenesis [26, 27]. In addition, neurodegenerative processes in the cortex and septohippocampal system can result in complex central dysrhythmia [28] particularly affecting theta and gamma activity.…”

Transcriptional signatures of brain aging and Alzheimer’s disease: What are our rodent models telling us?

“…Profiles of normal aging in rats [15–18], mice [19, 20], and humans [21–24] were selected. For AD comparison, idiopathic human AD [25–29], human Down’s syndrome [30] (as a human genetically induced model of AD-like pathology), as well five transgenic mouse AD models (Alzforum naming conventions): J20 (PDGF-APPSw,Ind) [31], Tg2576 [32], 3xTg [29], 5xFAD [33], and CK-p25 [34], were selected.…”