P2‐360: Growth factor neuroprotection in Alzheimer's disease: Long‐term effects of AAV2‐BDNF gene delivery in the entorhinal cortex of non‐human primates

Abstract

deleting these protease genes on memory deficits in the AD mouse model expressing human APP containing the WT beta-secretase site sequence and the London gamma-secretase site (APPWT/Lon mice), as well as the effects of administering the cysteine protease inhibitor E64d on memory deficits in that model. Methods: Firstly, transgenic APPWT/Lon mice with deletion of the cathepsin B or BACE1 gene were generated. Secondly, APPWT/Lonmicewere treated with E64d by oral administration. Both gene deletion and E64d treated animals were assessed for memory deficits by the Morris water maze test, for brain amyloid plaques by immunohistophathology, and for brain Abeta peptides and APP-derived fragments by ELISA and western analyses. Results: Knockout of the CatB gene in the APPWT/Lon mice improved memory deficits and altered the pattern of Abeta-related biomarkers in a manner consistent with CatB having WT beta-secretase activity. But deletion of the BACE1 gene had no effect on these parameters in the APPWT/Lon mice. These data are the first to show that knockout of a putative beta-secretase gene results in improved memory in an AD animal model expressing the WT beta-secretase site sequence of APP, present in the majority of AD patients. Furthermore, treatment of these mice with E64d, by oral administration, resulted in improvedmemory deficits and reduced brain Abeta.Conclusions: CatB may be an effective drug target and E64d may be an effective oral therapeutic agent for improving memory deficits in the majority of AD patients.