Cleavage of Tau by calpain in Alzheimer's disease: the quest for the toxic 17 kD fragment.
In: Neurobiology of aging, Jg. 32 (2011), Heft 1, S. 1-14
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Zugriff:
The amyloid cascade hypothesis of Alzheimer's disease (AD) posits that the generation of β-amyloid (Aβ) 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 Aβ-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 Aβ oligomers, but also by other cell stressors, e.g., thapsigargin (a Ca(2+)-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 Aβ-induced toxicity, leaving open the possibility that upstream calpain activation might cause both Tau fragmentation and toxicity.
(Copyright © 2010 Elsevier Inc. All rights reserved.)
Titel: |
Cleavage of Tau by calpain in Alzheimer's disease: the quest for the toxic 17 kD fragment.
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Autor/in / Beteiligte Person: | Garg, S ; Timm, T ; Mandelkow, EM ; Mandelkow, E ; Wang, Y |
Zeitschrift: | Neurobiology of aging, Jg. 32 (2011), Heft 1, S. 1-14 |
Veröffentlichung: | New York : Elsevier ; <i>Original Publication</i>: Fayetteville, N.Y. : Ankho International., 2011 |
Medientyp: | academicJournal |
ISSN: | 1558-1497 (electronic) |
DOI: | 10.1016/j.neurobiolaging.2010.09.008 |
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