Role of caspase-3 in tau truncation at D421 is restricted in transgenic mouse models for tauopathies |
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Authors: | Qipeng Zhang&dagger ,Xiaoguang Zhang&Dagger ,Jie Chen&dagger ,Yanying Miao&dagger , Anyang Sun&dagger |
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Affiliation: | Institute of Neurobiology, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China; Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China |
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Abstract: | Truncated tau is widely detected in Alzheimer's disease brain, and caspase-3 has been considered as a major executioner for tau truncation at aspartate421 (D421), according to its capability of cleaving recombinant tau in vitro . Here we investigated the relationship between D421 truncated tau and caspase-3 in two transgenic mouse models for tauopathies. In adult transgenic mice, activated caspase-3 could not be detected in neurons containing truncated tau, with the exception of a few glia-like cells or neurons in postnatal mice. Caspase-3 expression exhibited a dramatic decrease at the early development stage, and kept at constantly low levels during adult stages in both wild type and transgenic mice. On the other hand, co-incubating brain homogenates from adult tau transgenic mice and ethanol-treated postnatal mice promoted tau truncation at D421, which was mildly reduced by caspase inhibitor, but completely suppressed by phosphatase inhibitor, indicating that hyperphosphorylated tau becomes a poor substrate for truncation at D421. Taken together, our study shows that insufficient caspase-3 expression and hyperphosphorylated status of tau in the adult transgenic mouse brain restrict caspase-3 as an efficient enzyme for tau truncation in vivo . Clearly, there is a caspase-3 independent mechanism responsible for tau truncation at D421 in these models. |
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Keywords: | Alzheimer's disease caspase-3 tau truncation |
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