Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity and memory in mouse models of Alzheimer’s disease

Abstract

Neuronal protein synthesis is essential for long-term memory consolidation. Conversely, dysregulation of protein synthesis has been implicated in a number o neurodegenerative disorders, including Alzheimer's disease (AD). Several types of cellular stress trigger the activation of protein kinases that converge on the phosphorylation of eukaryotic translation initiation facor 2 α (eIF2α-P). This leads to attenuation of cap-dependent mRNA translation, a component of the integrated stress response (ISR). We show that AD brains exhibit increased eIF2α-P and reduced eIF2B, key components of the eIF2 translation initiation complex. We further demonstrate that attenuating the ISR wit the small molecule compound ISRIB (ISR inhibitor) rescues hippocampal protein synthesis and corrects impaired synaptic plasticity and memory in mouse models of AD. Our findings suggest that attenuating eIF2α-P-mediated translational inhibition may comprise an effective approach to alleviate cognitive decline in AD.

Early and late chaperone intervention therapy boosts XBP1s and ADAM10, restores proteostasis, and rescues learning in Alzheimer’s Disease mice

“…Critically, several studies have shown that reducing UPR activity or modulating the UPR improves memory in AD models (Halliday et al, 2015;Moreno et al, 2012;Ricobaraza et al, 2012). It has been shown that inhibiting phosphorylation of eIF2a, downstream of PERK and responsible for attenuating global translation, improves memory and synaptic plasticity in models of AD (Halliday et al, 2017;Moreno et al, 2012;Oliveira et al, 2021). Another study demonstrated that ATF4 is linked to impaired memory and synaptic plasticity (Costa-Mattioli et al, 2009).…”