Our recent review article discusses the potential of targeting caspase-2 (Casp2) in developing treatments for Alzheimer’s disease and related dementias (ADRD).
Traditional therapies focusing on amyloid-β plaques and tau tangles have been largely ineffective, prompting researchers to explore common signaling pathways contributing to synaptic dysfunction in these diseases. In this article, we highlight the cleavage of tau by Casp2, which leads to a toxic fragment (Δtau314) that disrupts synaptic transmission by promoting the internalization of AMPA receptors. Inhibiting Casp2 could restore synaptic function and improve cognitive deficits associated with ADRD. Our initial medicinal chemistry efforts to create selective peptidomimetic Casp2 inhibitors are presented, with our promising results indicating that these inhibitors may enhance memory and synaptic health in preclinical models. Overall, our research emphasizes the need for effective therapies that address the underlying mechanisms of ADRD, particularly through the modulation of Casp2 activity.
