eIF2-dependent translation initiation: Memory consolidation and disruption in Alzheimer's disease

Abstract

Memory storage is a conserved survivability feature, present in virtually any complex species. During the last few decades, much effort has been devoted to understanding how memories are formed and which molecular switches define whether a memory should be stored for a short or a long period of time. Among these, de novo protein synthesis is known to be required for the conversion of short- to long-term memory. There are a number translational control pathways involved in synaptic plasticity and memory consolidation, including the phosphorylation of the eukaryotic initiation factor 2 alpha (eIF2α), which has emerged as a critical molecular switch for long-term memory consolidation. In this review, we discuss findings pertaining to the requirement of de novo protein synthesis to memory formation, how local dendritic and axonal translation is regulated in neurons, and how these can influence memory consolidation. We also highlight the importance of eIF2α-dependent translation initiation to synaptic plasticity and memory formation. Finally, we contextualize how aberrant phosphorylation of eIF2α contributes to Alzheimer's disease (AD) pathology and how preventing disruption of eIF2-dependent translation may be a therapeutic avenue for preventing and/or restoring memory loss in AD.

Keywords: Alzheimer’s disease; EIF2α; Integrated stress response; MRNA translation; Memory consolidation; Protein synthesis.

Figure 1.. Local protein synthesis alters synapse function.

Postsynaptic protein synthesis (left inset) can be regulated by both ionotropic and metabotropic glutamate receptors, represented here as NMDAR and mGluRs, at excitatory synapses. Translation also can be stimulated by activation of the tyrosine kinase (TyK) receptor TrkB, via brain-derived neurotrophic factor (BDNF). The stimulation of protein synthesis by activation of these receptors is thought to mediate de novo production of AMPAR subunits that assemble into functional receptors that can then be expressed in the postsynaptic density, thereby strengthening that synapse. Notably, it has been suggested that the process of receptor exocytosis is also dependent on protein synthesis. On the other side of the synapse, local protein synthesis in the presynaptic terminal (right inset) may be regulated by retrograde signals such as endocannabinoids that are produced postsynaptically. It is not known whether action potentials can increase protein synthesis. Once translation is enhanced presynaptically, it is believed to play a role in controlling the recycling pool and fusion of neurotransmitter vesicles to the presynaptic membrane. Figure generated with Biorender.

Figure 2.. The Integrated Stress Response.

In the figure, the ISR is depicted by red arrows, while normal translation initiation via eIF2 is shown in black arrows. The eIF2α kinases PERK (localized in the endoplasmic reticulum), PKR, GCN2 and HRI sense specific cellular stress signals and dimerize, thereby promoting their kinase activity to phosphorylate eIF2 on its alpha subunit. Once phosphorylated, eIF2α inhibits the GDP-GTP exchange by the eIF2B complex and thus the ternary initiation complex (TIC) formation, reducing the formation of the 40S preinitiation complex, ultimately blocking protein synthesis. Importantly, ISRIB is capable of boosting protein synthesis independently of eIF2α phosphorylation, since it promotes the GEF activity of eIF2B. However, the downregulation of translation results in the increased translation of a subset of mRNAs with specific 5’UTR elements, including ATF4. Once translated, ATF4 migrates to the nucleus and transcribes a subset of genes that are responsible for responding to cellular stress and for feedback control of the ISR. Amongst these genes, PPP1R15A is transcribed and its protein product, GADD34, dephosphorylates eIF2α. When unphosphorylated, eIF2 binds to eIF2B, which exchanges a GDP for a GTP. The newly formed TIC binds to the 40S preinitiation complex, providing the ^MettRNA-Met necessary for the scanning ribosome to initiate translation. Once the start codon is found, eIF2 is released, and the 80S complex is formed. Figure generated with Biorender.

Figure 3.. The reciprocal relationship between the amyloidogenic processing of APP and disrupted translation in Alzheimer’s disease.

The amyloid cascade is triggered by the sequential cleavage of amyloid precursor protein (APP) by its secretases. This generates amyloid beta (Aβ) peptides that quickly start to aggregate, generating first soluble Aβ oligomers (AβOs) and then fibrils that will accumulate in the brain parenchyma and form amyloid plaques. Notably, AβOs are known to be powerful neurotoxic molecules that bind to different neuronal receptors and induce a series of harmful events. Among these, AβOs enhance the neuronal levels of eIF2α-P through the activation of PKR. Furthermore, evidence suggests that PERK and GCN2 may also play a role in the chronic elevation of eIF2α-P. Chronic increases in eIF2α-P results in impaired protein synthesis, leading to the translation of specific mRNAs with specialized 5’UTRs, including BACE1, the first secretase that cleaves APP. This sequence of events could trigger a cycle where the amyloidogenic processing enhances eIF2α-P, which then blocks general protein synthesis and promotes amyloidogenic processing by increasing the translation of BACE1. Figure generated with Biorender.