期刊
NEUROBIOLOGY OF AGING
卷 32, 期 1, 页码 1-14出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2010.09.008
关键词
Tau; Amyloid A beta; Calpain; Fragmentation; Toxicity; Neurodegeneration
资金
- EU
- Breuer Foundation
- BMBF
The amyloid cascade hypothesis of Alzheimer's disease (AD) posits that the generation of beta-amyloid (A beta) triggers Tau neurofibrillary pathology. Recently a 17 kD calpain-induced Tau fragment, comprising residues 45-230 (molecular weight [MW], 18.7 kD), was proposed to mediate A beta-induced toxicity. Here, we demonstrate that the 17 kD fragment is actually much smaller, containing residues 125-230 (molecular weight, 10.7 kD). Inducing Tau phosphorylation by okadaic acid or mimicking phosphorylation by Glu mutations at the epitopes of Alzheimer-diagnostic antibodies AT100/AT8/PHF1 could not prevent the generation of this fragment. The fragment can be induced not only by A beta oligomers, but also by other cell stressors, e.g., thapsigargin (a Ca2+-ATPase inhibitor) or glutamate (an excitatory neurotransmitter). However, overexpression of neither Tau(45-230) nor Tau(125-230) fragment is toxic to Chinese hamster ovary (CHO) cells, neuroblastoma cells (N2a) or primary hippocampal neurons. Finally, the calpain-induced fragment can be observed both in Alzheimer's disease brains and in control normal human brains. We conclude that the 17 kD Tau fragment is not a mediator of A beta-induced toxicity, leaving open the possibility that upstream calpain activation might cause both Tau fragmentation and toxicity. (C) 2011 Elsevier Inc. All rights reserved.
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