SERP1 is an assembly regulator of γ-secretase in metabolic stress conditions.

The enzyme gamma-secretase generates beta-amyloid peptides by cleaving amyloid protein precursor (APP); the aggregation of these peptides is associated with Alzheimer's disease (AD). Despite the development of various gamma-secretase regulators, their clinical use is limited by coincident disruption of other gamma-secretase-regulated substrates, such as Notch. Using a genome-wide functional screen of gamma-secretase activity in cells and a complementary DNA expression library, we found that SERP1 is a previously unknown gamma-secretase activator that stimulates AD generation in cells experiencing endoplasmic reticulum (ER) stress, such as is seen with diabetes. SERP1 interacted with a subcomplex of gamma-secretase (APH1A/NCT) through its carboxyl terminus to enhance the assembly and, consequently, the activity of the gamma-secretase holoenzyme complex. In response to ER stress, SERP1 preferentially recruited APP rather than Notch into the gamma-secretase complex and enhanced the subcellular localization of the complex into lipid rafts, increasing AD production. Moreover, SERP1 abundance, gamma-secretase assembly, and AD production were increased both in cells exposed to high amounts of glucose and in diabetic AD model mice. Conversely, AD production was decreased by knocking down SERP1 in cells or in the hippocampi of mice. Compared to postmortem samples from control individuals, those from patients with AD showed increased SERP1 expression in the hippocampus and parietal lobe. Together, our findings suggest that SERP1 is an APP-biased regulator of gamma-secretase function in the context of cell stress, providing a possible molecular explanation for the link between diabetes and sporadic AD.