Lysosomal dysfunction in Down syndrome and Alzheimer mouse models is caused by v-ATPase inhibition by Tyr <sup>682</sup> -phosphorylated APP βCTF
Eunju Im, Ying Jiang, Philip Stavrides, Sandipkumar Darji, Hediye Erdjument‐Bromage, Thomas A. Neubert, Jun Yong Choi, Jerzy Węgiel, Ju‐Hyun Lee, Ralph A. Nixon
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 682 YENPTY 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 Tyr 682 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 phosphorylation below normal constitutive levels boosts v-ATPase assembly and activity, suggesting that v-ATPase may also be modulated tonically by phospho-APP-βCTF. Elevated APP-βCTF Tyr 682 phosphorylation in two mouse AD models similarly disrupts v-ATPase function. These findings offer previously unknown insight into the pathogenic mechanism underlying faulty lysosomes in all forms of AD.