Caspase‑2 Inhibitor Blocks Tau Truncation and Restores Excitatory Neurotransmission in Neurons Modeling FTDP-17 Tauopathy

Gurpreet Singh, Peng Liu, Katherine R. Yao, Jessica M. Strasser, Chris Hlynialuk, Kailee Leinonen-Wright, Peter J. Teravskis, Jessica M. Choquette, Junaid Ikramuddin, Merlin Bresinsky, Kathryn M. Nelson, Dezhi Liao, Karen H. Ashe, Michael A. Walters, Steffen Pockes

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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 Δtau314, 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 Δtau314. 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.

Original languageEnglish (US)
Pages (from-to)1549-1557
Number of pages9
JournalACS Chemical Neuroscience
Volume13
Issue number10
DOIs
StatePublished - May 18 2022

Bibliographical note

Publisher Copyright:
© 2022 American Chemical Society.

Keywords

  • Alzheimer’s disease
  • Caspase-2
  • dementia
  • neurodegenerative disorders
  • tauopathies

Fingerprint

Dive into the research topics of 'Caspase‑2 Inhibitor Blocks Tau Truncation and Restores Excitatory Neurotransmission in Neurons Modeling FTDP-17 Tauopathy'. Together they form a unique fingerprint.

Cite this