A distinct ER/IC γ-secretase competes with the proteasome for cleavage of APP

The deposition of amyloid-beta peptides (A beta) in senile plaques (SPs) is a central pathological feature of Alzheimer's disease (AD). Since SPs are composed predominantly of A beta 1-42, which is more amyloidogenic in vitro, the enzymes involved in generating A beta 1-42 may be particularly important to the pathogenesis of AD. In contrast to A beta 1-40. which is generated in the trans-Golgi network and other cytoplasmic organelles, intracellular A beta 1-42 is produced in the endoplasmic reticulum/intermediate compartment (ER/IC), where it accumulates in a stable insoluble pool. Since this pool of insoluble A beta 1-42 may play a critical role in AD amyloidogenesis, we sought to determine how the production of intracellular A beta is regulated. Surprisingly, the production of insoluble intracellular A beta 1-42 was increased by a putative gamma-secretase inhibitor as well as by an inhibitor of the proteasome. We further demonstrate that this increased generation of A beta 1-42 in the ER/IC is due to a reduction in the turnover of A beta-containing APP C-terminal fragments. We conclude that the proteasome is a novel site for degradation of ER/IC-generated APP fragments. Proteasome inhibitors may augment the availability of APP C-terminal fragments for gamma-secretase cleavage and thereby increase production of ABI-42 in the ER/IC. Based on the organelle-specific differences in the generation of AB by gamma-secretase, we conclude that intracellular ER/IC-generated A beta 1-42 and secreted A beta 1-40 are produced by different gamma-secretases. Further, the fact that a putative gamma-secretase inhibitor had opposite effects on the production of secreted and intracellular A beta may have important implications for AD drug design.