임은주 (Nathan S. Kline Institute, New York University Grossman School of Medicine, 현 아밀로이드 솔루션) | 한빛사논문 > 한빛사

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Nathan S. Kline Institute, New York University Grossman School of Medicine, 현 아밀로이드 솔루션

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Sci. Adv., Jul 28 2023, 9 (30) eadg1925 | https://doi.org/10.1126/sciadv.adg1925 Lysosomal dysfunction in Down syndrome and Alzheimer mouse models is caused by v-ATPase inhibition by Tyr682-phosphorylated APP βCTF

Eunju Im ¹^,2, Ying Jiang ^1,2, Philip H Stavrides¹, Sandipkumar Darji ¹, Hediye Erdjument-Bromage ^3,4, Thomas A Neubert ^3,4, Jun Yong Choi ^5,6, Jerzy Wegiel⁷, Ju-Hyun Lee ^1,2, Ralph A Nixon ^1,2,3,8*

¹Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA.

²Department of Psychiatry, New York University Grossman School of Medicine, New York, NY 10016, USA.

³Department of Cell Biology, New York University Grossman School of Medicine, New York, NY 10016, USA.

⁴Kimmel Center for Biology and Medicine at the Skirball Institute, New York University Grossman School of Medicine, New York, NY, 10016, USA.

⁵Department of Chemistry and Biochemistry, Queens College, Queens, NY 11367, USA.

⁶Ph.D. Programs in Chemistry and Biochemistry, The Graduate Center of the City University of New York, New York, NY 10016, USA.

⁷Department of Developmental Neurobiology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.

⁸NYU Neuroscience Institute, New York University Grossman School of Medicine, New York, NY 10016, USA.

^*Corresponding author : 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 ⁶⁸²YENPTY 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.

논문정보

형식Research article
게재일2023년 07월 (BRIC 등록일 2024-01-22)
연구진국외 연구진
분야 생명과학 > 신경생물학

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