The results demonstrate that APP673 regulates APP processing and the BACE1 cleavage site selection is critical for amyloidogenesis in AD pathogenesis, and implicate a pharmaceutical potential for targeting the APP673 site for AD drug development.<b>SIGNIFICANCE STATEMENT</b> β-site APP cleaving enzyme 1 (BACE1) is essential for amyloid β protein production.
These data suggest that, selectively in neurons, relatively high levels of BACE1 activity lead to substrate pressure on FAD-mutant GS complexes, promoting CNS Aβ42 accumulation.
We have tested the functional significance of BACE1 processing of APP using App-Swedish (App<sup>s</sup> ) knock-in rats, which carry an App mutation that causes familial Alzheimer's disease (FAD) in humans.