Singh, Gurpreet and Liu, Peng and Yao, Katherine R. and Strasser, Jessica M. and Hlynialuk, Chris and Leinonen-Wright, Kailee and Teravskis, Peter J. and Choquette, Jessica M. and Ikramuddin, Junaid and Bresinsky, Merlin and Nelson, Kathryn M. and Liao, Dezhi and Ashe, Karen H. and Walters, Michael A. and Pockes, Steffen (2022) Caspase-2 Inhibitor Blocks Tau Truncation and Restores Excitatory Neurotransmission in Neurons Modeling FTDP-17 Tauopathy. ACS CHEMICAL NEUROSCIENCE, 13 (10). pp. 1549-1557. ISSN 1948-7193,
Full text not available from this repository. (Request a copy)Abstract
Synaptic and cognitive deficits mediated by a severe reduction in excitatory neurotransmission caused by a disproportionate accumulation of the neuronal protein tau in dendritic spines is a fundamental mechanism that has been found repeatedly in models of tauopathies, including Alzheimer's disease, Lewy body dementia, frontotemporal dementia, and traumatic brain injury. Synapses thus damaged may contribute to dementia, among the most feared cause of debilitation in the elderly, and currently there are no treatments to repair them. Caspase-2 (Casp2) is an essential component of this pathological cascade. Although it is believed that Casp2 exerts its effects by hydrolyzing tau at aspartate-314, forming Delta tau314, it is also possible that a noncatalytic mechanism is involved because catalytically dead Casp2 is biologically active in at least one relevant cellular pathway, that is, autophagy. To decipher whether the pathological effects of Casp2 on synaptic function are due to its catalytic or noncatalytic properties, we discovered and characterized a new Casp2 inhibitor, compound 1 [pKi (Casp2) = 8.12], which is 123-fold selective versus Casp3 and >2000-fold selective versus Casp1, Casp6, Casp7, and Casp9. In an in vitro assay based on Casp2-mediated cleavage of tau, compound 1 blocked the production of Delta tau314. Importantly, compound 1 prevented tau from accumulating excessively in dendritic spines and rescued excitatory neurotransmission in cultured primary rat hippocampal neurons expressing the P301S tau variant linked to FTDP-17, a familial tauopathy. These results support the further development of small-molecule Casp2 inhibitors to treat synaptic deficits in tauopathies.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CELL-DEATH; FRONTOTEMPORAL DEMENTIA; DENDRITIC SPINES; APOPTOSIS; MISLOCALIZATION; DYSFUNCTION; MUTATION; FAMILY; NEDD2; GENE; Caspase-2; Alzheimer ? s disease; neurodegenerative disorders; tauopathies; dementia |
| Subjects: | 500 Science > 540 Chemistry & allied sciences |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 07 Feb 2024 07:08 |
| Last Modified: | 07 Feb 2024 07:08 |
| URI: | https://pred.uni-regensburg.de/id/eprint/57661 |
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