Lysosomal dysfunction in Down syndrome and Alzheimer mouse models is caused by v-ATPase inhibition by Tyr⁶⁸²-phosphorylated APP βCTF.

ABSTRACT: Lysosome dysfunction arises early and propels Alzheimer's disease (AD). Herein, we show that amyloid precursor protein (APP), linked to early-onset AD in Down syndrome (DS), acts directly via its β-C-terminal fragment (βCTF) to disrupt lysosomal vacuolar (H⁺)-adenosine triphosphatase (v-ATPase) and acidification. In human DS fibroblasts, the phosphorylated ⁶⁸²YENPTY internalization motif of APP-βCTF binds selectively within a pocket of the v-ATPase V0a1 subunit cytoplasmic domain and competitively inhibits association of the V1 subcomplex of v-ATPase, thereby reducing its activity. Lowering APP-βCTF Tyr⁶⁸² phosphorylation restores v-ATPase and lysosome function in DS fibroblasts and in vivo in brains of DS model mice. Notably, lowering APP-βCTF Tyr^682<

SUBMITTER: Im E 

PROVIDER: S-EPMC10371027 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature