Deletion of the eIF2α Kinase GCN2 Fails to Rescue the Memory Decline Associated with Alzheimer’s Disease

Abstract

Emerging evidence suggests that dysregulated translation through phosphorylation of eukaryotic initiation factor-2α (eIF2α) may contribute to Alzheimer’s disease (AD) and related memory impairments. However, the underlying mechanisms remain unclear. Here, we crossed knockout mice for an eIF2α 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 β-secretase enzyme BACE1 and the CREB repressor ATF4 concomitant with a dramatic increase of eIF2α 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 β-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 eIF2α 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 eIF2α kinase under the physiological condition, whereas blocking the GCN2 pathway under exposure to significant β-amyloidosis rather aggravates eIF2α phosphorylation leading to BACE1 and ATF4 elevations in AD.

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

“…Genotyping was performed by PCR analysis of tail DNA and all experiments were done blind with respect to the genotype of mice. In this study, we investigated the effects of PERK haploinsufficiency in 5XFAD mice at 8–9 months of age, which exhibit significant elevations in BACE1 and ATF4 expression (Devi and Ohno, 2010a; Devi and Ohno, 2013a; Zhao et al, 2007). Since our previous study shows that there is no sex difference in cerebral Aβ levels in 5XFAD mice except for the younger age (≤3 months) (Oakley et al, 2006), a similar number of males and females were used for the experiments.…”

eIF2 Dephosphorylation in Basolateral Amygdala Mediates Reconsolidation of Drug Memory

“…*p Ͻ 0.05 compared with the no-retrieval (NoR) group. ugation for 8 min at 4°C to remove any insoluble materials, including nuclei and large debris, and the supernatant containing cytosolic proteins and light membrane fraction was collected based on previous studies (Jiang et al, 2010;Devi and Ohno, 2013). All of the procedures were performed at 0 -4°C.…”

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

“…A link between Alzheimer’s disease (AD) and reduced global translation was established in 1989, when Langstrom et al demonstrated that polysomes from the cortices of AD patients were associated with less RNA than those from controls. Subsequently, increased levels of p-eIF2α were found in the cortex and hippocampus of AD patients and in AD mouse models (Chang et al, 2002b; Devi and Ohno, 2013; Hoozemans et al, 2009; Kim et al, 2007; Lewerenz and Maher, 2009; Ma et al, 2013; Mouton-Liger et al, 2012; O’Connor et al, 2008; Page et al, 2006; Stutzbach et al, 2013; Unterberger et al, 2006). In addition to AD, p-eIF2α levels are elevated in the brain or spinal cord of patients and mice with prion disease (Unterberger et al, 2006), amyotrophic lateral sclerosis (ALS; Ilieva et al, 2007), Parkinson’s disease (PD; Hoozemans et al, 2007, 2012), Huntington’s disease (HD; Leitman et al, 2014), and various tauopathies (Köhler et al, 2014; Nijholt et al, 2012; Radford et al, 2015; Stutzbach et al, 2013; Unterberger et al, 2006).…”

“…Similarly, a reduction in p-eIF2α levels and improved spatial memory were observed when Gcn2 was deleted in an AD mouse model. In contrast, GCN2 activation appears to be protective in a different AD mouse model; in this context, loss of Gcn2 increases p-PERK, increasing levels of p-eIF2α and the burden of Aβ plaques in the brain (Devi and Ohno, 2013). …”