Energy Deprivation Elevates BACE1 Protein Levels and Promotes Amyloidogenesis via EIF2alpha PhosphorylationPublic Deposited
The cause(s) of Aβ overproduction and accumulation in SAD are unknown; however, several lines of evidence indicate that impaired energy metabolism in the brain may be involved. Furthermore, the rate-limiting enzyme in Aβ production, BACE1, is elevated in SAD brains around amyloid plaques, indicating that BACE1 may also play a causal role in SAD pathogenesis. Here, we show evidence that BACE1 is directly elevated in response to energy deprivation, both in vitro and in vivo. This appears to occur through a translational mechanism, previously unknown to regulate BACE1--- stress-induced phosphorylation of the eukaryotic translation initation factor 2α (eIF2α-P). In support of a role for eIF2α phosphorylation in SAD pathogenesis, pharmacological induction of eIF2α phosphorylation is directly amyloidogenic in vitro. Chronic energy deprivation in APP-overexpressing mice elevates BACE1 protein levels post-transcriptionally, eIF2α-P levels, total Aβ levels, and accelerates amyloid plaque pathology in the brain. Interestingly, BACE1 and eIF2α-P are both elevated in APP-overexpressing mice compared to non-transgenic, indicating that BACE1, eIF2α-P, and Aβ may operate together in a positive feedback loop that may further exacerbate amyloid pathology. Importantly, BACE1 protein levels, eIF2α-P levels, and amyloid load were all significantly correlated in human AD brains, indicating that these molecular pathways may play in important role in the development of SAD.