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

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, 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/amyloid precursor-like protein 2 (APLP2) deficient mouse embryonic fibroblast cells is more vulnerable to leakage caused by oxidative stress, adeno-associated virus, or tau incubation, compared with that in WT controls. The increased vulnerability of the endo-lysosomal 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 dKO and that of WT mouse embryonic fibroblast cells. Furthermore, we uncovered higher APP expression in primary neurons from the cerebellum of mouse embryos compared with 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 member in the regulation of endo-lysosomal membrane vulnerability.