Expertise
Caspase-2 as a Therapeutic Target
For many years, the protease Caspase-2 (Casp2) was considered a redundant initiator and/or effector of apoptosis and was, therefore, not initially considered a priority target for drug development. However, in the context of Alzheimer’s disease, a role for Casp2 was proposed more than 20 years ago and more recently confirmed in animal models of Alzheimer’s disease and frontotemporal dementia.
Casp2-specific inhibitors have not yet been tested in humans. Currently, there are no commercially available selective Casp2 inhibitors. The standard Casp2 inhibitors marketed for research use (e.g., Ac-VDVAD-CHO and z-VDVAD-fmk) are non-selective. They have poor bioavailability and strong inhibitory effects on Caspase-3 (Casp3). Selective pharmacological targeting of Casp2 has long been considered challenging due to the structural similarity between the catalytic domains of caspases. Specifically, Casp2 shares the closest cleavage specificity similarities with Casp3 and Casp7, and to a lesser extent with Casp8. Therefore, designing selective inhibitors for Casp2 is a challenge.
Research conducted at Inserm (Paris, France) has led to the design and evaluation of a series of peptidomimetics derived from the canonical pentapeptide VDVAD, combining a potent irreversible warhead (proven safe in humans) with non-natural structures conferring specificity and bioavailability to Casp2. The most potent caspase-2 inhibitor (Casp2i) peptidomimetic, LJ2a, inhibits human Casp2 with an extremely high inactivation rate. LJ3a is the most selective inhibitor, with an inactivation rate nearly 1000 times higher for Casp2 compared to Casp3
Role of Caspase-2 in the Cytotoxic Effects of Aβ and Tau and Protection of Neurons by the Selective Inhibitor LJ3a
Recent studies have highlighted the crucial role of Casp2 in the cytotoxicity induced by amyloid β (Aβ) peptides and the Tau protein, two key players in the pathology of Alzheimer’s disease.
Amyloid-β (Aβ) oligomers are central pathogenic proteins in Alzheimer's disease. Aβ induces synapse loss through rapid Casp2 activation. At higher concentrations, Aβ also induces neuronal death. Pozueta et al. (2013) demonstrated that Caspase-2 is necessary for the dendritic and behavioral alterations induced by Aβ in transgenic APP mouse models. Their study showed that inhibition of Caspase-2 could mitigate these effects, suggesting a central role of this enzyme in mediating Aβ-induced neuronal damage.
Similarly, Zhao et al. (2016) discovered that Caspase-2 cleaves the Tau protein, a process that reversibly impairs memory in a mouse model of frontotemporal dementia. This cleavage of Tau by Caspase-2 leads to the formation of toxic fragments that disrupt synaptic function and contribute to neurodegeneration.
More recently, a promising advancement has been made with the development of the selective Caspase-2 inhibitor, LJ3a. In primary hippocampal neurons treated with Aβ oligomers, submicromolar concentrations of LJ3a prevent synapse loss (Bosc et al., 2022). LJ3a also protects human neurons, differentiated from embryonic stem cells, from the cytotoxic effects of Aβ. This protection is attributed to the inhibition of Caspase-2 activity, thereby preventing the apoptotic processes triggered by Aβ.
These findings underscore the importance of Caspase-2 in the pathology of Alzheimer’s disease and open new therapeutic perspectives. The selective inhibition of Caspase-2 by molecules such as LJ3a could offer an effective strategy to protect neurons from Aβ and Tau-induced damage, thereby slowing the progression of neurodegeneration and improving cognitive functions in patients with Alzheimer’s disease.