Tau overload associated insufficient lysosomal hydrolysis activity through deacidification of lysosomes

Neuronal tau overload and lysosomal dysfunction are two pathological features in Alzheimer’s disease. Here, by ultra-high-resolution-fluorescence imaging and ultrastructural imaging, the lysosomes were observed larger in size, less numerous, perinuclear distributed and inhomogeneous in electron density in tau overloaded neurons of mice and tau overexpressed HEK293 (HEK293tau) cells. In these lysosomes there existed lots of accumulations and less active hydrolases, which was further confirmed by an elevated lysosomal pH and decreased levels of fluorescence-labeled hydrolysate inside lysosomes in living HEK293tau cells. The assembly of vacuolar-type proton-pumping ATPases (V-ATPases) on lysosomal membrane is crucial for maintaining the acidity of lysosome. Although the proteome and Western blotting data showed increased V-ATPase subunits in HEK293tau cells, we detected the abnormal binding of ATP6V1B2, an important V-ATPase subunit, to tau. It was suggested tau overload might destabilize lysosomal pH by binding with ATP6V1B2 and blocking V-ATPases assembly on the lysosomal membrane.