Mechanisms of amyloid-?34 generation indicate a pivotal role for BACE1 in amyloid homeostasis

The beta-site amyloid precursor protein (APP) cleaving enzyme (BACE1) was discovered due to its "amyloidogenic" activity which contributes to the production of amyloid-beta (A?) peptides. However, BACE1 also possesses an "amyloidolytic" activity, whereby it degrades longer A? peptides into a non-toxic A?34 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 A?34. 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 A?34 levels. At the cellular level, a mislocalization of surplus BACE1 caused a reduction in A?34 levels. To align the role of ?-secretase in this pathway, we silenced Presenilin (PS) expression and identified PS2-?-secretase as the main ?-secretase that generates A?40 and A?42 peptides serving as substrates for BACE1's amyloidolytic cleavage to generate A?34.