Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 Jan;32(1):1-14.
doi: 10.1016/j.neurobiolaging.2010.09.008. Epub 2010 Oct 18.

Cleavage of Tau by Calpain in Alzheimer's Disease: The Quest for the Toxic 17 kD Fragment

Affiliations

Cleavage of Tau by Calpain in Alzheimer's Disease: The Quest for the Toxic 17 kD Fragment

Sarika Garg et al. Neurobiol Aging. .

Abstract

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.

Similar articles

See all similar articles

Cited by 47 articles

See all "Cited by" articles

Publication types

MeSH terms

LinkOut - more resources

Feedback