Tau deletion impairs intracellular β-amyloid-42 clearance and leads to more extracellular plaque deposition in gene transfer models

Background: Tau is an axonal protein that binds to and regulates microtubule function. Hyper-phosphorylation of Tau reduces its binding to microtubules and it is associated with beta-amyloid deposition in Alzheimer's disease. Paradoxically, Tau reduction may prevent beta-amyloid pathology, raising the possibility that Tau mediates intracellular A beta clearance. The current studies investigated the role of Tau in autophagic and proteasomal intracellular A beta 1-42 clearance and the subsequent effect on plaque deposition. Results: Tau deletion impaired A beta clearance via autophagy, but not the proteasome, while introduction of wild type human Tau into Tau(-/-) mice partially restored autophagic clearance of A beta 1-42, suggesting that exogenous Tau expression can support autophagic A beta 1-42 clearance. Tau deletion impaired autophagic flux and resulted in A beta 1-42 accumulation in pre-lysosomal autophagic vacuoles, affecting A beta 1-42 deposition into the lysosome. This autophagic defect was associated with decreased intracellular A beta 1-42 and increased plaque load in Tau(-/-) mice, which displayed less cell death. Nilotinib, an Abl tyrosine kinase inhibitor that promotes autophagic clearance mechanisms, reduced A beta 1-42 only when exogenous human Tau was expressed in Tau(-/-) mice. Conclusions: These studies demonstrate that Tau deletion affects intracellular A beta 1-42 clearance, leading to extracellular plaque.