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

Molecular Neurodegeneration

Charbel Moussa²  Joel Schachter¹  Wenqiang Chen³  Michaeline Hebron²  Irina Lonskaya² 

[1] Neuroscience Discovery, Merck Research Laboratories, 770 Sunneytown Pike, West Point, PA 19486, USA;Department of Neuroscience, Laboratory for Dementia and Parkinsonism, Georgetown University Medical Center, 3970 Reservoir RD, Washington, DC 20057, USA;Department of Traditional Chinese Medicine, Xuanwu Hospital, Capital Medical University, Beijing 100053, China

关键词: Proteasome;    Autophagy;    Plaques;    Intracellular Aβ1-42;    Tau;   

Others  :  1132673
DOI  :  10.1186/1750-1326-9-46

 received in 2014-08-20, accepted in 2014-10-21,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Lonskaya et al.; licensee BioMed Central Ltd.

【 图 表 】

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