Zhao X, Kotilinek LA, Smith B, Hlynialuk C, Zahs K, Ramsden M, Cleary J, Ashe KH. Caspase-2 Cleavage of Tau Reversibly Impairs Memory. Nature Medicine. 2016;22(11):1268-1276. PMID: 27723722. DOI: 10.1038/nm.4199.
Summary
This landmark paper identified caspase-2 cleavage of tau at Asp314 as a mechanism that produces a soluble tau fragment associated with memory impairment. The authors showed that this tau species, later referred to as Δtau314, promotes tau mislocalization to dendritic spines and disrupts synaptic function. Importantly, reducing or blocking this cleavage improved memory-related phenotypes, supporting the idea that tau-mediated cognitive dysfunction can be reversible. The study directly connected caspase-2 activity to synaptic and behavioral deficits.
Key Findings
- Caspase-2 cleaves tau at Asp314.
- The resulting Δtau314 fragment impairs synaptic and memory function.
- Tau cleavage promoted mislocalization to dendritic spines.
- Memory impairment was reversible when the pathway was blocked.
Impact on the Caspase-2/Tau Program
This paper defined caspase-2 as a therapeutic target for tau-mediated cognitive dysfunction. It provided the mechanistic basis for developing caspase-2 inhibitors as disease-modifying or cognition-restoring agents.
