| First Author | Im E | Year | 2023 |
| Journal | Sci Adv | Volume | 9 |
| Issue | 30 | Pages | eadg1925 |
| PubMed ID | 37494443 | Mgi Jnum | J:338544 |
| Mgi Id | MGI:7513461 | Doi | 10.1126/sciadv.adg1925 |
| Citation | Im E, et al. (2023) Lysosomal dysfunction in Down syndrome and Alzheimer mouse models is caused by v-ATPase inhibition by Tyr(682)-phosphorylated APP betaCTF. Sci Adv 9(30):eadg1925 |
| abstractText | 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 beta-C-terminal fragment (betaCTF) to disrupt lysosomal vacuolar (H(+))-adenosine triphosphatase (v-ATPase) and acidification. In human DS fibroblasts, the phosphorylated (682)YENPTY internalization motif of APP-betaCTF 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-betaCTF Tyr(682) phosphorylation restores v-ATPase and lysosome function in DS fibroblasts and in vivo in brains of DS model mice. Notably, lowering APP-betaCTF 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-betaCTF. Elevated APP-betaCTF 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. |
