Antagonists targeting eEF2 kinase rescue multiple aspects of pathophysiology in Alzheimer’s disease model mice

Abstract

It is imperative to develop novel therapeutic strategies for Alzheimer's disease (AD) and related dementia syndromes based on solid mechanistic studies. Maintenance of memory and synaptic plasticity relies on de novo protein synthesis, which is partially regulated by phosphorylation of eukaryotic elongation factor 2 (eEF2) via its kinase eEF2K. Abnormally increased eEF2 phosphorylation and impaired mRNA translation have been linked to AD. We recently reported that prenatal genetic suppression of eEF2K is able to prevent aging-related cognitive deficits in AD model mice, suggesting the therapeutic potential of targeting eEF2K/eEF2 signaling in AD. Here, we tested two structurally distinct small-molecule eEF2K inhibitors in two different lines of AD model mice after the onset of cognitive impairments. Our data revealed that treatment with eEF2K inhibitors improved AD-associated synaptic plasticity impairments and cognitive dysfunction, without altering brain amyloid β (Aβ) and tau pathology. Furthermore, eEF2K inhibition alleviated AD-associated defects in dendritic spine morphology, post-synaptic density formation, protein synthesis, and dendritic polyribosome assembly. Our results may offer critical therapeutic implications for AD, and the proof-of-principle study indicates translational implication of inhibiting eEF2K for AD and related dementia syndromes.

Homozygous knockout of eEF2K alleviates cognitive deficits in APP/PS1 Alzheimer’s disease model mice independent of brain amyloid β pathology

“…Both WT and eEF2K −/− mice exhibited normal learning during the training, indicated by marked day-to-day decreases in escape latency during the acquisition phase (Figures 2D,E). Consistent with previous studies (Zimmermann et al, 2020;Kasica et al, 2022), APP mice demonstrated longer escape latency, indicating a cognitive impairment (Figures 2D,E). Importantly, impaired learning observed in the APP mice was alleviated in the APP/eEF2K −/− mice, as demonstrated by improved day-to-day escape latency (Figures 2D,E).…”

“…Moreover, substantial evidence indicates that eEF2K activity is not required for development or cell survival under physiological conditions. Transgenic mice with global knockout of eEF2K or wild-type mice treated with the chronic treatment of eEF2K inhibitors appear normal in numerous measurements of basic biological functions during development (Heise et al, 2017;Ma, 2021;Kasica et al, 2022). Thus, eEF2K could be a "safe" target, which is important for AD patients who usually need to take medicine continuously over a long period.…”

“…Thus, eEF2K knockout prevented impairment of long-term recognition memory in the APP/PS1 AD model mice. Moreover, we used the hidden-platform MWM task to assess spatial learning and memory (Zimmermann et al, 2020;Kasica et al, 2022). Both WT and eEF2K −/− mice exhibited normal learning during the training, indicated by marked day-to-day decreases in escape latency during the acquisition phase (Figures 2D,E).…”

“…Distance traveled and velocity of movement during the probe trial were unaltered across the four genotypes (Supplementary Figure 2B). We also examined potential learning and memory-independent effects of eEF2K knockout (e.g., swimming ability, vision, and motivation) through the visible maze task (Zimmermann et al, 2020;Kasica et al, 2022). No differences in latency to locate the visible platform were observed across all the genotypes (Figure 2G).…”

“…Previous studies from our lab reported hyperphosphorylation of eEF2 in both post mortem hippocampal tissue from AD patients and transgenic mouse models (Ma et al, 2014;Jan et al, 2017;Beckelman et al, 2019). Suppression of eEF2K activity via pharmacological inhibitors or siRNA method alleviated amyloid β (Aβ)-induced synaptic failure and neurotoxicity (Ma et al, 2014;Jan et al, 2017;Kasica et al, 2022). The study from Jan et al (2017) suggested the beneficial effects of eEF2K inhibition on Aβ-induced neurotoxicity were mediated via the interactions between eEF2K and the transcription factor nuclear erythroid 2-related factor (NRF2) antioxidant pathway.…”