| First Author | Devi L | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 10 | Pages | e77335 |
| PubMed ID | 24146979 | Mgi Jnum | J:209106 |
| Mgi Id | MGI:5565668 | Doi | 10.1371/journal.pone.0077335 |
| Citation | Devi L, et al. (2013) Deletion of the eIF2alpha Kinase GCN2 fails to rescue the memory decline associated with Alzheimer's disease. PLoS One 8(10):e77335 |
| abstractText | Emerging evidence suggests that dysregulated translation through phosphorylation of eukaryotic initiation factor-2alpha (eIF2alpha) may contribute to Alzheimer's disease (AD) and related memory impairments. However, the underlying mechanisms remain unclear. Here, we crossed knockout mice for an eIF2alpha kinase (GCN2: general control nonderepressible-2 kinase) with 5XFAD transgenic mice, and investigated whether GCN2 deletion affects AD-like traits in this model. As observed in AD brains, 5XFAD mice recapitulated significant elevations in the beta-secretase enzyme BACE1 and the CREB repressor ATF4 concomitant with a dramatic increase of eIF2alpha phosphorylation. Contrary to expectation, we found that GCN2(-/-) and GCN2(+/-) deficiencies aggravate rather than suppress hippocampal BACE1 and ATF4 elevations in 5XFAD mice, failing to rescue memory deficits as tested by the contextual fear conditioning. The facilitation of these deleterious events resulted in exacerbated beta-amyloid accumulation, plaque pathology and CREB dysfunction in 5XFAD mice with GCN2 mutations. Notably, GCN2 deletion caused overactivation of the PKR-endoplasmic reticulum-related kinase (PERK)-dependent eIF2alpha phosphorylation pathway in 5XFAD mice in the absence of changes in the PKR pathway. Moreover, PERK activation in response to GCN2 deficiency was specific to 5XFAD mice, since phosphorylated PERK levels were equivalent between GCN2(-/-) and wild-type control mice. Our findings suggest that GCN2 may be an important eIF2alpha kinase under the physiological condition, whereas blocking the GCN2 pathway under exposure to significant beta-amyloidosis rather aggravates eIF2alpha phosphorylation leading to BACE1 and ATF4 elevations in AD. |
