Lysosomal dysfunction in Down syndrome and Alzheimer mouse models is caused by v-ATPase inhibition by Tyr ⁶⁸² -phosphorylated APP βCTF

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.

Reduction of Cystatin B results in increased cathepsin B activity in disomic but not Trisomy21 human cellular and mouse models

“…Thus, another mechanism likely results in the insensitivity of CatB activity to CSTB abundance in the context of trisomy 21. Trisomy of Hsa21 results in perturbations to endo-lysosomal biology, in part because of an effect of APP-CTF on v-ATPase acidification [34].…”

Transcriptome analysis of early-onset familial Alzheimer’s disease and Sanfilippo syndrome zebrafish models reveals commonalities in disease mechanisms

“…The upregulation of these genes may reflect how the cells constituting these bulk brain RNA-seq samples are attempting to restore the normal pH of defective lysosomes to maintain cellular homeostasis. Lysosomal acidification defects have been detected in PSEN1- deficient and primary PSEN1 -EOfAD fibroblasts (105), as well as several other models of AD mutations (106–109). Lysosomal pH was not detected as significantly altered in MPS IIIA mouse embryonic fibroblasts (110).…”

dAux orchestrates the phosphorylation-dependent assembly of the lysosomal V-ATPase in glia and contributes to α-synuclein degradation

“…Dysregulation of V-ATPase activity has been shown in many neurodegenerative disorders including PD 19,43 . For instance, the modification, protein level, or protein-protein interaction of the V0a1 subunit is critical for the pathology of different types of neurodegenerative diseases 44–47 . The PD risk factor leucine-rich repeat kinase 2 (LRRK2) also regulates V0a1 protein level and localization 45 .…”