Pockes S, Walters MA, Ashe KH. Targeting Caspase-2 Interactions with Tau in Alzheimer’s Disease and Related Dementias. Translational Research. 2023;254:34-40. PMID: 36328077. DOI: 10.1016/j.trsl.2022.10.009.
Summary
This review synthesized evidence supporting caspase-2 as a therapeutic target for Alzheimer’s disease and related dementias. The authors summarized the discovery of caspase-2-mediated tau cleavage, the role of Δtau314 in synaptic and cognitive dysfunction, human biomarker evidence, and emerging medicinal chemistry approaches. The review positioned caspase-2 inhibition as a translational strategy to restore synaptic function rather than simply reduce classical pathology. It also highlighted challenges in developing selective, brain-penetrant inhibitors.
Key Findings
- The review integrated mechanistic, biomarker, and drug-discovery evidence.
- Caspase-2/tau interactions were linked to synaptic dysfunction.
- Human disease relevance was emphasized.
- Medicinal chemistry challenges and opportunities were outlined.
Impact on the Caspase-2/Tau Program
This paper serves as a translational rationale for the therapeutic program. It connects biological discovery, human validation, and inhibitor development into a coherent drug-discovery strategy.