NDST3 suppression restores lysosomal acidification and ameliorates amyloid-β and MAPT/tau pathology in Alzheimer's disease

Background: Impairment of lysosomal acidification has recently been identified as a critical driver of amyloid-β and MAPT/tau pathology in Alzheimer's disease (AD). Restoring lysosomal acidification is a promising strategy for AD treatment. N-deacetylase and N-sulfotransferase 3 (NDST3) is a newly discovered tubulin deacetylase that regulates lysosomal acidification by influencing the recruitment of V-ATPase V1 subunits to lysosomes. Nevertheless, the role of NDST3 in AD remains entirely unexplored. Methods: We began by comparing the effects of NDST3 and histone deacetylase 6 (HDAC6), a well-known tubulin deacetylase with established roles in AD, on lysosomal acidification. Using HT22 cell-based models of AD, we knocked down NDST3 to examine its role in lysosomal acidification and degradative function in the context of this disease. We also evaluated the expression profile of NDST3 in both in vitro and in vivo models of AD. Finally, we investigated the consequences of NDST3 suppression on lysosomal acidity and related AD pathological features in the hippocampi of 3 × Tg-AD mice. Results: NDST3 differs from HDAC6 in the subcellular spatial patterns of catalyzing microtubule deacetylation but parallels HDAC6 in regulating lysosomal pH. In HT22 cells with APP695Swe overexpression, knockdown of NDST3 lowered lysosomal pH by promoting the assembly of the V-ATPase holoenzyme on the lysosomal membrane and enhanced the autophagic degradation of aberrant Aβ and MAPT/tau. Notably, NDST3 levels were found to be elevated in the brains of AD models and patients. Reducing NDST3 expression in the hippocampi of 3 × Tg-AD mice facilitated lysosomal reacidification, which decreased the abnormal accumulation of amyloid plaques and MAPT/tau tangles, mitigated neuronal damage, and ameliorated cognitive deficits. Conclusions: Our study identified NDST3 as a key factor regulating lysosomal acidity in AD. Suppressing NDST3 restores lysosomal function in AD and protects against AD pathology, highlighting NDST3 as a promising therapeutic target for AD.