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

Lysosome dysfunction arises early and propels Alzheimers Disease (AD). Herein, we show that amyloid precursor protein (APP), linked to early-onset AD in Down Syndrome (DS), acts directly via its {beta}-C-terminal fragment ({beta}CTF) to disrupt lysosomal v-ATPase and acidification. In human DS fibroblasts, the phosphorylated 682YENPTY internalization motif of APP-{beta}CTF 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-{beta}CTF Tyr682 phosphorylation restores v-ATPase and lysosome function in DS fibroblasts and in vivo in brains of DS model mice. Notably, lowering APP-{beta}CTF Tyr682 phosphorylation below normal constitutive levels boosts v-ATPase assembly and activity, suggesting that v-ATPase may also be modulated tonically by phospho-APP-{beta}CTF. Elevated APP-{beta}CTF Tyr682 phosphorylation in two mouse AD models similarly disrupts v-ATPase function. These findings offer new insight into the pathogenic mechanism underlying faulty lysosomes in all forms of AD.