Role of caspase-3 in tau truncation at D421 is restricted in transgenic mouse models for tauopathies.
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.
Zhang
Qipeng
Q
Institute of Neurobiology, Fudan University, Shanghai, China.
Zhang
Xiaoguang
X
Chen
Jie
J
Miao
Yanying
Y
Sun
Anyang
A
D000818:Animals; D001224:Aspartic Acid / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3 / Q000737:chemistry / Q000502:physiology*; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D024801:Tauopathies / Q000201:enzymology* / Q000235:genetics; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D016875:tau Proteins; D001224:Aspartic Acid; D053148:Caspase 3