Deletion of the Cathepsin B Gene Improves Memory Deficits in a Transgenic Alzheimer's Disease Mouse Model Expressing AβPP Containing the Wild-Type β-Secretase Site Sequence

Therapeutic agents that improve the memory loss of Alzheimer's disease (AD) may eventually be developed if drug targets are identified that improve memory deficits in appropriate AD animal models. One such target is beta-secretase which, in most AD patients, cleaves the wild-type (WT) beta-secretase site sequence of the amyloid-beta protein precursor (A beta PP) to produce neurotoxic amyloid-beta (A beta). Thus, an animal model representing most AD patients for evaluating beta-secretase effects on memory deficits is one that expresses human A beta PP containing the WT beta-secretase site sequence. BACE1 and cathepsin B (CatB) proteases have beta-secretase activity, but gene knockout studies have not yet validated that the absence of these proteases improves memory deficits in such an animal model. This study assessed the effects of deleting these protease genes on memory deficits in the AD mouse model expressing human A beta PP containing the WT beta-secretase site sequence and the London gamma-secretase site (A beta PPWT/Lon mice). Knockout of the CatB gene in the A beta PPWT/Lon mice improved memory deficits and altered the pattern of A beta-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 A beta PPWT/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 A beta PP, present in the majority of AD patients. CatB may be an effective drug target for improving memory deficits in most AD patients.