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.
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.