Tau deletion impairs intracellular ß-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 ß-amyloid deposition in Alzheimer's disease. Paradoxically, Tau reduction may prevent ß-amyloid pathology, raising the possibility that Tau mediates intracellular Aß clearance. The current studies investigated the role of Tau in autophagic and proteasomal intracellular Aß1-42 clearance and the subsequent effect on plaque deposition. RESULTS: Tau deletion impaired Aß clearance via autophagy, but not the proteasome, while introduction of wild type human Tau into Tau-/- mice partially restored autophagic clearance of Aß1-42, suggesting that exogenous Tau expression can support autophagic Aß1-42 clearance. Tau deletion impaired autophagic flux and resulted in Aß1-42 accumulation in pre-lysosomal autophagic vacuoles, affecting Aß1-42 deposition into the lysosome. This autophagic defect was associated with decreased intracellular Aß1-42 and increased plaque load in Tau-/- mice, which displayed less cell death. Nilotinib, an Abl tyrosine kinase inhibitor that promotes autophagic clearance mechanisms, reduced Aß1-42 only when exogenous human Tau was expressed in Tau-/- mice. CONCLUSIONS: These studies demonstrate that Tau deletion affects intracellular Aß1-42 clearance, leading to extracellular plaque.