Cysteine protease inhibitor, e64d, of cathepsin b reduces pglu-abeta and abeta, and improves memory deficits in the applon mouse model of ad

Background: Pyroglutamate amyloid-beta peptides (pGlu-Abeta) are particularly pernicious forms of Abeta. pGlu-Abeta and full-length Abeta peptides accumulate in Alzheimer’s disease (AD) brains, leading to severe memory deficits. pGlu-Abeta peptides are N-terminally truncated forms of full-length Abeta peptides with modification of the N-terminal glutamate to form pGlu-Abeta(3-40/42). The prominent presence of pGlu-Abeta in AD brains and involvment pGlu-Abeta to initiate formation of oligomeric neurotoxic Abeta forms may be key in AD. Our recent research indicates the key role of the alternative beta-secretase cathepsin B (CatB) in the production of pGlu-Abeta and Abeta (Hook et al., 2014, in press; Kindy et al., 2012), suggesting that inhibitors of CatB can reduce pGlu-Abeta and Abeta. Therefore, this study investigated the cysteine protease inhibitor E64d, that inhibits CatB, for its effectives in reducing Abeta peptide forms and improving memory deficits in APPLon AD mice, which express APP-695 and have the wild-type (wt) beta-secretase activity present in most AD patients.