Nα-p-tosyl-L-lysine chloromethyl ketone and Nα-p-tosyl-L-phenylalanine chloromethyl ketone are potent inhibitors of β-amyloid-induced lamin fragmentation.

Cellular toxicity induced by β-Amyloid (Aβ) peptide involves lamin A and lamin B fragmentation (LF),and inhibiting LF mitigates cytotoxicity; therefore, we aimed to identify novel inhibitors of Aβ-induced LF. We identified Nα-p-tosyl-L-lysine chloromethyl ketone (TLCK) and Nα-p-tosyl-L-phenylalanine chloromethyl ketone (TPCK) as inhibitors that reduce Aβ42-induced LF, alter nuclear morphology, and activate apoptotic caspases in Aβ42-treated cells. TLCK demonstrated a suppressive effect on Aβ42-induced cell death, whereas TPCK, which is inherently cytotoxic, did not. Both TLCK and TPCK decreased the activation and activity of cathepsin L (CL) which known to be implicated in catalyzing Aβ42-induced LF. TLCK and TPCK have a suppressive effect on Aβ42-induced LF in which CL is implicated. Our findings will contribute to the further investigation of Aβ-related pathology and cell death induced by other agents inhibited by TLCK and TPCK. While our findings highlight potential mechanisms underlying AD-related pathology in HeLa and SH-SY5Y cells but future validation in primary neurons, astrocytes, or animal models will be necessary to confirm these observations.