| First Author | Devi L | Year | 2014 |
| Journal | Neurobiol Aging | Volume | 35 |
| Issue | 10 | Pages | 2272-81 |
| PubMed ID | 24889041 | Mgi Jnum | J:218077 |
| Mgi Id | MGI:5616515 | Doi | 10.1016/j.neurobiolaging.2014.04.031 |
| Citation | Devi L, et al. (2014) PERK mediates eIF2alpha phosphorylation responsible for BACE1 elevation, CREB dysfunction and neurodegeneration in a mouse model of Alzheimer's disease. Neurobiol Aging 35(10):2272-81 |
| abstractText | Emerging evidence suggests that aberrant phosphorylation of eukaryotic initiation factor-2alpha (eIF2alpha) may induce synaptic failure and neurodegeneration through persistent translational inhibition of global protein synthesis. However, elevated phospho-eIF2alpha also paradoxically causes translational activation of a subset of messenger RNAs such as the beta-secretase enzyme, beta-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 eIF2alpha 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-eIF2alpha pathway, as evidenced by significant reductions in phosphorylation of PERK and eIF2alpha, 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-beta 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. |
