@article{71fbf464024c4f3780bbc947e3dc3d68,
title = "Appoptosin-Mediated Caspase Cleavage of Tau Contributes to Progressive Supranuclear Palsy Pathogenesis",
abstract = "Progressive supranuclear palsy (PSP) is a movement disorder characterized by tau neuropathology where the underlying mechanism is unknown. An SNP (rs1768208 C/T) has been identified as a strong risk factor for PSP. Here, we identified a much higher T-allele occurrence and increased levels of the pro-apoptotic protein appoptosin in PSP patients. Elevations in appoptosin correlate with activated caspase-3 and caspase-cleaved tau levels. Appoptosin overexpression increased caspase-mediated tau cleavage, tau aggregation, and synaptic dysfunction, whereas appoptosin deficiency reduced tau cleavage and aggregation. Appoptosin transduction impaired multiple motor functions and exacerbated neuropathology in tau-transgenic mice in a manner dependent on caspase-3 and tau. Increased appoptosin and caspase-3-cleaved tau were also observed in brain samples of patients with Alzheimer's disease and frontotemporal dementia with tau inclusions. Our findings reveal a novel role for appoptosin in neurological disorders with tau neuropathology, linking caspase-3-mediated tau cleavage to synaptic dysfunction and behavioral/motor defects.",
author = "Yingjun Zhao and Tseng, {I. Chu} and Heyser, {Charles J.} and Edward Rockenstein and Michael Mante and Anthony Adame and Qiuyang Zheng and Timothy Huang and Xin Wang and Arslan, {Pharhad E.} and Paramita Chakrabarty and Chengbiao Wu and Guojun Bu and Mobley, {William C.} and Zhang, {Yun wu} and {St. George-Hyslop}, Peter and Eliezer Masliah and Paul Fraser and Huaxi Xu",
note = "Funding Information: We thank T. Golde at University of Florida for AAV packaging, P. Davies at Albert Einstein College of Medicine for providing PHF-1 antibody, L. Hazrati at University of Toronto for providing human brain specimens, R. Kaufman at Sanford Burnham Prebys Medical Discovery Institute for providing control adenovirus, and S. Tu and L. Lacarra at Sanford Burnham Prebys Medical Discovery Institute for technical assistance and helpful discussion. This work was supported in part by grants from National Institute of Health (R01AG021173, R01AG038710, R01AG044420, and R01NS046673 to H.X.; R01AG18440, R01AG5131, R01AG11385, and R01NS076411 to E.M.; PN2 EY016525 and R01NS66072.to W.C.M.), Alzheimer{\textquoteright}s Association (H.X. and Y.-w.Z.), The Tanz Family Funds to H.X., and National Natural Science Foundation of China (91332114 and U1405222 to H.X.; 81225008, 81161120496, and 91332112 to Y.-w.Z.). Grant support for this study also comes from the Down Syndrome Research, Treatment Foundation (C.W., W.C.M.), the Larry L. Hillblom Foundation (C.W., W.C.M.), and Canadian Institutes of Health China-Canada AD Initiative (TAD-117950 to P.F. and P.S.G.). Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",
year = "2015",
month = sep,
day = "2",
doi = "10.1016/j.neuron.2015.08.020",
language = "English (US)",
volume = "87",
pages = "963--975",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "5",
}