Caspase‐2 Inhibition for Treatment of Alzheimer’s Disease

Background

The enzyme caspase‐2 plays a central role in cellular apoptosis and is involved in the early stages of β‐amyloid 42 and tau deposition, making it a promising therapeutic target for Alzheimer’s Disease (AD). Caspase‐2 is highly expressed in the brains of patients with AD (1, 4) and those with mild cognitive impairment, which often precedes AD. This indicates the upregulation of caspase‐2 early in disease progression, which is not observed in healthy adult brains (1‐3).

Method

New irreversible small peptidomimetics (LJ2a and LJ3a) inhibit human caspase‐2 with a remarkably high inactivation rate. (5) In primary hippocampal neurons treated with β‐amyloid oligomers, submicromolar concentrations of LJ2a and LJ3a prevent synapse loss. Using a tamoxifen‐inducible Cre system for the global removal of caspase‐2, a series of experiments were performed on mice stereotaxically injected with β‐amyloid 42. This model was used to validate caspase‐2 blockade by assessing the cellular specificity of caspase‐2 activation, the induction of downstream targets, and cell death marker expression via immunohistochemistry and western blot.

Result

Replication of these experiments remains underway.

Conclusion

Presentation of current data can inform the rationality for using caspase‐2 inhibitors as a therapeutic treatment.

References:

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3. Kumar, S., Kinoshita, M., Noda, M., Copeland, N. G. & Jenkins, N. A. Induction of apoptosis by the mouse Nedd2 gene, which encodes a protein similar to the product of the Caenorhabditis elegans cell death gene ced‐3 and the mammalian IL‐1 beta‐converting enzyme. Genes & development 8, 1613‐1626 (1994).

4. Liu, P. et al. A soluble truncated tau species related to cognitive dysfunction is elevated in the brain of cognitively impaired human individuals. Sci Rep 10, 3869, https://doi.org/10.1038/s41598‐020‐60777‐x (2020).

5. Bosc, E., Anastasie, J., Soualmia, F. et al. Genuine selective caspase‐2 inhibition with new irreversible small peptidomimetics. Cell Death Dis 13, 959. https://doi.org/10.1038/s41419‐022‐05396‐2 (2022).