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• W4281887789 abstract "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 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 new insight into the pathogenic mechanism underlying faulty lysosomes in all forms of AD." @default.
• W4281887789 created "2022-06-13" @default.
• W4281887789 creator A5011617410 @default.
• W4281887789 creator A5022090615 @default.
• W4281887789 creator A5049641549 @default.
• W4281887789 creator A5052509179 @default.
• W4281887789 creator A5055084400 @default.
• W4281887789 creator A5055455188 @default.
• W4281887789 creator A5067978392 @default.
• W4281887789 creator A5075397509 @default.
• W4281887789 creator A5077666007 @default.
• W4281887789 creator A5090266693 @default.
• W4281887789 date "2022-06-04" @default.
• W4281887789 modified "2023-09-29" @default.
• W4281887789 title "Lysosomal dysfunction in Down Syndrome and Alzheimer mouse models is caused by selective v-ATPase inhibition by Tyr⁶⁸²phosphorylated APP βCTF" @default.
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