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bioRxiv · 10.1101/2022.06.02.494546

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

Im, E.·Jiang, Y.·Stavrides, P.·Darji, S.·Erdjument-Bromage, H.·Neubert, T.·Bordi, M.·Choi, J. Y.·Lee, J.-H.·Nixon, R.
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Abstract

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.

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Im, E., Jiang, Y., Stavrides, P., Darji, S., Erdjument-Bromage, H., Neubert, T., Bordi, M., Choi, J. Y., Lee, J.-H., Nixon, R.. 2022-06-04. Lysosomal dysfunction in Down Syndrome and Alzheimer mouse models is caused by selective v-ATPase inhibition by Tyr682 phosphorylated APP βCTF. https://doi.org/10.1101/2022.06.02.494546

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