ABSTRACT
There is evidence that ß-secretase and amyloid precursor protein ß-C-terminal fragments (APP-CTF) are involved in the pathogenesis of Alzheimer's disease (AD). Previously, we have reported that N-benzyloxycarbonyl-Val-Leu-leucinal (zVLL-CHO) reduced APP ß-CTF accumulation in axonal swellings of degenerating neurons. Here, in an effort to discover more effective neuroprotective agents, we examined the effects of the ß-secretase inhibitors, H-KTEEISEVN-stat-VAEF-OH (VAEF) and H-EVNstatineVAEF-NH2 (GL-189) as well as zVLL-CHO on OA (okadaic acid)-induced neurodegeneration. Unexpectedly, we found that pretreatment with zVLL-CHO (1 µM) protected neurons after OA treatment, whereas both VAEF and GL-189 lacked neuroprotective effects. Interestingly, 1 µM zVLL-CHO did not inhibit ß-secretase. We previously reported that calpain is activated by OA treatment and calpain inhibitors protect against OA-induced neurodegeneration. The data presented here show that pretreatment with 1 µM zVLL-CHO decreased the levels of calpain-cleaved α-spectrin with a concomitant decrease in LDH release and an increase in average dendritic branch length compared to neurons treated with OA alone. These findings suggest that zVLL-CHO protects against OA-induced neurodegeneration via calpain inactivation.
