PERK mediates eIF2α phosphorylation responsible for BACE1 elevation, CREB dysfunction and neurodegeneration in a mouse model of Alzheimer's disease

Abstract

Emerging evidence suggests that aberrant phosphorylation of eukaryotic initiation factor-2α (eIF2α) may induce synaptic failure and neurodegeneration through persistent translational inhibition of global protein synthesis. However, elevated phospho-eIF2α also paradoxically causes translational activation of a subset of mRNAs such as the β-secretase enzyme BACE1 and CREB repressor ATF4. Therefore, we tested whether genetic reduction of the eIF2α kinase PERK may prevent these deleterious events and mitigate Alzheimer’s disease (AD)-like neuropathology and cognitive impairments in the 5XFAD mouse model. PERK haploinsufficiency blocked overactivation of the PERK-eIF2α pathway, as evidenced by significant reductions in phosphorylation of PERK and eIF2α, in 5XFAD mice. PERK haploinsufficiency was sufficient to rescue memory deficits and cholinergic neurodegeneration in this AD model. Notably, PERK haploinsufficiency also prevented BACE1 elevations, resulting in reduced levels of amyloid-β peptides and plaque burden in 5XFAD mice. Moreover, CREB dysfunction was restored in PERK+/−·5XFAD mice concomitant with reversal of ATF4 upregulation. Together, these findings suggest that PERK may be a disease-modifying therapeutic target to prevent multiple memory-disrupting mechanisms associated with AD.

Regulation of mRNA Translation in Neurons—A Matter of Life and Death

“…Aβ increases p-PKR and p-eIF2α in cultured neurons, and a reduction in PKR diminished Aβ-associated toxicity (Chang et al, 2002a). Contextual fear learning and mGluR-dependent long-term depression, both of which are affected upon eIF2α phosphorylation dysregulation, are impaired in AD mouse models, and the reduction of PERK levels rescues these deficits (Costa-Mattioli et al, 2005, 2007; Devi and Ohno, 2014; Trinh et al, 2014; Yang et al, 2016; Zhu et al, 2011). The contribution of GCN2 to eIF2α phosphorylation in AD is less clear.…”

Unfolded Protein Response and PERK Kinase as a New Therapeutic Target in the Pathogenesis of Alzheimer’s Disease

“…There is a body of evidence suggesting that the occurrence of AD mutations is closely linked to ER stress and as a result, an increased amount of phosphorylated eukaryotic initiation factor-2α (eIF2α), BACE1 and ATF4 in the brain tissue of AD patients [60]. Furthermore, study by Hoozemans et al .…”

“…This is the most important enzyme associated with the production of the longer form of Aβ [60] as well as ATF4 that is associated with the development of AD [72]. The levels of eIF2α with phosphorylated subunit α are significantly higher in the AD brains and positively correlate with expression levels of BACE1 and Aβ plaque aggregation [53].…”

“…The levels of eIF2α with phosphorylated subunit α are significantly higher in the AD brains and positively correlate with expression levels of BACE1 and Aβ plaque aggregation [53]. These phenomena reveal that overactivated phosphorylation of eIF2α and may be the main cause of memory impairment associated with AD pathogenesis not only by arresting the general protein synthesis, but also by increasing the production of Aβ42 through secretase β [60] (Fig. 4).…”

Cholinergic degeneration in early stages of Alzheimer’s disease: Loss of cholinergic phenotype or loss of cells?

“…However, elevated phosphorylation of eIF2α paradoxically causes translational activation of a subset of mRNAs such as the β-secretase enzyme, β-site APP-cleaving enzyme 1 (BACE1) and cAMP response element binding protein (CREB) repressor, activating transcription factor 4 (ATF4). In a 5×FAD mouse model, increased phospho-eIF2α level is associated with cholinergic dysfunction but not cell loss [62,84]. Unfortunately, it is not clear to which extent the data from AD brain autopsy and transgenic models could be correlated with selective lesion or loss of cholinergic neurons.…”