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Mol Neurodegener. 2014 Nov 10;9:46. doi: 10.1186/1750-1326-9-46.

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

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Department of Neuroscience, Laboratory for Dementia and Parkinsonism, Georgetown University Medical Center, 3970 Reservoir RD, Washington, DC 20057, USA.



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 β-amyloid deposition in Alzheimer's disease. Paradoxically, Tau reduction may prevent β-amyloid pathology, raising the possibility that Tau mediates intracellular Aβ clearance. The current studies investigated the role of Tau in autophagic and proteasomal intracellular Aβ1-42 clearance and the subsequent effect on plaque deposition.


Tau deletion impaired Aβ clearance via autophagy, but not the proteasome, while introduction of wild type human Tau into Tau-/- mice partially restored autophagic clearance of Aβ1-42, suggesting that exogenous Tau expression can support autophagic Aβ1-42 clearance. Tau deletion impaired autophagic flux and resulted in Aβ1-42 accumulation in pre-lysosomal autophagic vacuoles, affecting Aβ1-42 deposition into the lysosome. This autophagic defect was associated with decreased intracellular Aβ1-42 and increased plaque load in Tau-/- mice, which displayed less cell death. Nilotinib, an Abl tyrosine kinase inhibitor that promotes autophagic clearance mechanisms, reduced Aβ1-42 only when exogenous human Tau was expressed in Tau-/- mice.


These studies demonstrate that Tau deletion affects intracellular Aβ1-42 clearance, leading to extracellular plaque.

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