Singh G, Liu P, Yao KR, Strasser JM, Hlynialuk C, Leinonen-Wright K, Teravskis PJ, Choquette JM, Ikramuddin J, Bresinsky M, Nelson KM, Liao D, Ashe KH, Walters MA, Pockes S. Caspase-2 Inhibitor Blocks Tau Truncation and Restores Excitatory Neurotransmission in Neurons Modeling FTDP-17 Tauopathy. ACS Chemical Neuroscience. 2022;13(10):1549-1557. PMID: 35522720. DOI: 10.1021/acschemneuro.2c00100.
Summary
This paper evaluated a caspase-2 inhibitor in neuronal models of FTDP-17 tauopathy. The authors showed that pharmacological inhibition of caspase-2 reduced tau truncation and restored deficits in excitatory neurotransmission. The work provided functional evidence that inhibiting caspase-2 can affect a disease-relevant neuronal phenotype, not simply block an isolated biochemical reaction. It bridged the mechanistic tau-cleavage hypothesis with medicinal chemistry efforts to develop caspase-2-directed therapeutic agents.
Key Findings
- Caspase-2 inhibition reduced tau truncation.
- Neuronal excitatory transmission was restored.
- The study used disease-relevant tauopathy neuronal models.
- Pharmacological intervention supported target druggability.
Impact on the Caspase-2/Tau Program
This paper provided key functional validation for caspase-2 inhibitors. It linked compound activity to restoration of synaptic physiology, an important translational endpoint for cognition-focused therapy.