Caspase‐2 Inhibition for Treatment of Alzheimer’s Disease

Abstract

AbstractBackgroundThe 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).MethodNew 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.ResultReplication of these experiments remains underway.ConclusionPresentation of current data can inform the rationality for using caspase‐2 inhibitors as a therapeutic treatment.