| First Author | Ulku I | Year | 2023 |
| Journal | Sci Rep | Volume | 13 |
| Issue | 1 | Pages | 2216 |
| PubMed ID | 36750595 | Mgi Jnum | J:334802 |
| Mgi Id | MGI:7433805 | Doi | 10.1038/s41598-023-28846-z |
| Citation | Ulku I, et al. (2023) Mechanisms of amyloid-beta34 generation indicate a pivotal role for BACE1 in amyloid homeostasis. Sci Rep 13(1):2216 |
| abstractText | The betasite amyloid precursor protein (APP) cleaving enzyme (BACE1) was discovered due to its "amyloidogenic" activity which contributes to the production of amyloid-beta (Abeta) peptides. However, BACE1 also possesses an "amyloidolytic" activity, whereby it degrades longer Abeta peptides into a nontoxic Abeta34 intermediate. Here, we examine conditions that shift the equilibrium between BACE1 amyloidogenic and amyloidolytic activities by altering BACE1/APP ratios. In Alzheimer disease brain tissue, we found an association between elevated levels of BACE1 and Abeta34. In mice, the deletion of one BACE1 gene copy reduced BACE1 amyloidolytic activity by ~ 50%. In cells, a stepwise increase of BACE1 but not APP expression promoted amyloidolytic cleavage resulting in dose-dependently increased Abeta34 levels. At the cellular level, a mislocalization of surplus BACE1 caused a reduction in Abeta34 levels. To align the role of gamma-secretase in this pathway, we silenced Presenilin (PS) expression and identified PS2-gamma-secretase as the main gamma-secretase that generates Abeta40 and Abeta42 peptides serving as substrates for BACE1's amyloidolytic cleavage to generate Abeta34. |
