PERK mediates eIF2α phosphorylation responsible for BACE1 elevation, CREB dysfunction and neurodegeneration in a mouse model of Alzheimer's disease.
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 messenger RNAs 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). 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.
['Devi|Latha|L|', 'Ohno|Masuo|M|']
D000544:Alzheimer Disease D053829:Amyloid Precursor Protein Secretases D000818:Animals D016282:Aspartic Acid Endopeptidases D017362:Cyclic AMP Response Element-Binding Protein D004195:Disease Models, Animal D015852:Eukaryotic Initiation Factor-2 D008810:Mice, Inbred C57BL D008822:Mice, Transgenic D009410:Nerve Degeneration D010766:Phosphorylation D019892:eIF-2 Kinase
PERK BACE1 CREB ATF4 5XFAD Amyloid-β Cholinergic neuron Fear conditioning Learning and memory elF2α