Identification of a Caspase-Derived N-Terminal Tau Fragment in Cellular and Animal Alzheimer's Disease Models

Authors

Troy T. Rohn, Boise State UniversityFollow

Document Type

Article

Publication Date

7-1-2008

DOI

http://dx.doi.org/10.1016/j.mcn.2008.03.011

Abstract

Biochemical modifications of tau proteins have been proposed to be among the earliest neurobiological changes in Alzheimer's disease (AD) and correlate better with cognitive symptoms than do beta-amyloid plaques. We have recently reported that adenovirus-mediated overexpression of the NH₂ 26–230aa tau fragment evokes a potent NMDA-mediated neurotoxic effect in primary neuronal cultures. In order to assess whether such N-terminal tau fragment(s) are indeed produced during apoptosis or neurodegeneration in vivo, we attempted to ascertain their presence in cell and animal models using an anti-tau antibody directed against the N-terminal sequence of human protein located downstream of the caspase(s)-cleavage site DRKD₂₅-QGGYTMHQDQ. We provide biochemical evidence that a caspase(s)-cleaved NH₂-terminal tau fragment of 20–22 kDa, consistent with the size of the NH₂ 26–230aa neurotoxic fragment of tau, is generated in vitro in differentiated human SH-SY5Y cells undergoing apoptosis by BDNF withdrawal or following treatment with staurosporine. In addition this NH₂-terminally cleaved tau fragment, whose expression correlates with a significant up-regulation of caspase(s) activity, is also specifically detected in vivo in the hippocampus of 15 month-old AD11 transgenic mice, a model in which a progressive AD-like neurodegeneration is induced by the expression of transgenic anti-NGF antibodies. The results support the idea that aberrant activation of caspase(s), following apoptotic stimuli or neurodegeneration insults, may produce one or more toxic NH₂ tau fragments, that further contribute to propagate and increase cellular dysfunctions in AD.

Comments

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Publication Information

Rohn, Troy T.. (2008). "Identification of a Caspase-Derived N-Terminal Tau Fragment in Cellular and Animal Alzheimer's Disease Models". Molecular and Cellular Neuroscience, 38(3), 381-392.