Journal
NEURON
Volume 87, Issue 5, Pages 963-975Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2015.08.020
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Funding
- National Institute of Health [R01AG021173, R01AG038710, R01AG044420, R01NS046673, R01AG18440, R01AG5131, R01AG11385, R01NS076411, PN2 EY016525, R01NS66072]
- Alzheimer's Association
- Tanz Family Funds
- National Natural Science Foundation of China [91332114, U1405222, 81225008, 81161120496, 91332112]
- Down Syndrome Research, Treatment Foundation
- Larry L. Hillblom Foundation
- Canadian Institutes of Health China-Canada AD Initiative [TAD-117950]
- MRC [MC_G1000734] Funding Source: UKRI
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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 proapoptotic 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.
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