Inhibition of caspases 3/6 and cathepsins L/B decreases apoptosis caused by laminopathy in Alzheimer’s disease

Background: Laminopathy is one of the pathological manifestations of Alzheimer’s disease, leading to neuron apoptosis. We aimed to evaluate the inhibitor enzymes potentially involved in laminopathy. Methods The mRNA expression of the cathepsins L and B, caspases 3 and 6, lamins b1 and b2, granzymes A and B, and lamins A and C were extracted and analyzed from GSE5281 and GSE28146 datasets. A total number of 143 ligands structurally similar to the inhibitors of selected enzymes were implemented through molecular docking. Subsequently, 100 ns molecular dynamics (MD) with NAMD and Martini 3 were performed for two selected ligands. Results The expression level of the mRNAs highlighted caspase 6 and lamin A/C upregulation in the hippocampus of the AD samples, in contrast to cathepsin B, lamin b2, and caspase 3. Moreover, there was a strong correlation between the expression level of cathepsin B, lamin A/C, and caspase 6 in the AD group. Besides, in exploring potential inhibitors for the enzymes involved in the laminopathy, molecules with PubChem id of 608841, and ChEMBL id of 550872 were selected. Eventually, the MD results suggested the molecule with PubChem id of 608841 to be more stable in complex with the receptor. Conclusion We indicate that lamins A/C, cathepsins B/L, caspase 6, and lamin b2 are associated with laminopathy as the potential factor of apoptosis in AD. We suggest that simultaneous inhibition of caspases 3/6 and cathepsins L/B may decrease the rate of apoptosis triggered by lamin degradation.