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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.

Author information

  • 1Department of Neuroscience, Laboratory for Dementia and Parkinsonism, Georgetown University Medical Center, 3970 Reservoir RD, Washington, DC 20057, USA. cem46@georgetown.edu.

Abstract

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 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.

RESULTS:

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.

CONCLUSIONS:

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

PMID:
25384392
PMCID:
PMC4247762
DOI:
10.1186/1750-1326-9-46
[PubMed - indexed for MEDLINE]
Free PMC Article
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