APP family is a regulator of endo-lysosomal membrane vulnerability.

Abstract

The amyloid precursor protein (APP) is cleaved by β- and γ-secretases, resulting in the generation of β-amyloid (Aβ). Aβ peptides accumulate in the brain of Alzheimer's disease (AD), and the removal of toxic Aβ species using antibodies slows the progression of the disease. However, the potential physiological function(s) of APP and its family members remains elusive. Various studies, including ours, reported that APP C99 is primarily processed by γ-secretase in the endo-lysosomal compartments. Here, we report using a series of complementary assays that the endo-lysosomal membrane in APP/APLP2-deficient mouse embryonic fibroblasts (MEFs) is more vulnerable to leakage caused by oxidative stress, adeno-associated virus (AAV), or tau incubation, compared to that in wild-type controls. The increased vulnerability of endo-lysosome membrane is, in part, rescued by APP overexpression, suggesting the contribution of both APP and APLP2. Mechanistically, we observed distinct lipid profiles, including increased cholesterol and Hex1Cer, between the membrane of APP/APLP2 knockout and that of WT MEF cells. Furthermore, we uncovered higher APP expression in primary neurons from the cerebellum of mouse embryos compared to those from the cortex, and the endo-lysosomal membrane in the cerebellum neurons is less vulnerable to leakage than that in the cortical neurons. Taken together, our findings suggest an unrecognized role of APP and its family members in the regulation of endo-lysosomal membrane vulnerability.