Engineering brain-penetrant and selective caspase-2 inhibitors for neurological disorders

• Applicant: Privatdozent Dr. Steffen Pockes
• Subject Area: Pharmacy ; Organic Molecular Chemistry - Synthesis and Characterisation
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 527849699

Our project seeks to repair synaptic transmission in Alzheimer's disease by targeting and inhibiting the enzyme caspase-2 (Casp2). It has already been shown that reduced Casp2 levels or the genetic absence of Casp2 better protect human neurons. The protein tau, which is present in the human brain and is actually responsible for stabilizing cytoskeletal proteins (microtubules), is cleaved by Casp2 in the brain, producing a specific cleavage product (Δtau314) tau314). This cleavage product leads to the destruction of synapses by accumulating in the dendritic spines, which ultimately leads to reduced brain performance. This critically disrupts neuronal communication at synapses. It has also been found that Δtau314) tau314 is increased threefold in brains of Alzheimer's patients. Based on these and other findings, we hypothesize that cognitive function is preserved in tauopathies such as Alzheimer's disease when Casp2 is prevented from cleaving tau. For this reason, there is an urgent need to develop selective agents to inhibit the enzyme caspase-2. In order to find an optimal drug, numerous prototypes need to be tested to gain important insights into efficacy, drug uptake, drug stability, mobility in the brain, and last but not least, side effect profile, which will be part of our study.

• DFG Programme: Research Grants