Response to: Zhou JW et al. (2012) J Alzheimers Dis 28, 471-480

1 February 2012

It is important to clarify, based upon the data presented, this paper’s conclusion that cathepsin B lacks “β-secretase activity” because the ambiguity of that statement could lead some readers to erroneously believe that the data show cathepsin B lacks the wild-type (WT) β-secretase activity that predominates in the common form of sporadic Alzheimer’s disease (AD). In fact, what this paper’s data show is that cathepsin B lacks Swedish mutant (Swe) β-secretase activity found in a very rare form of familial AD, and they say nothing about its WT β-secretase activity, which is the target activity for developing inhibitors to treat most AD patients. That is because the paper determined “β-secretase” activity using the NH2-Arg-GLu-(EDANS)-Glu-Val-Asn-Leu-Asp-Ala-Glyu-Phe-Lys(D-ABCYL)-Arg-COOH substrate, which contains the Swe mutations at the β-secretase cleavage site (Swe residues underlined). That sequence only detects Swe β-secretase activity, and no other substrate containing the WT β-secretase cleavage site was used. As correctly cited in the paper, cathepsin B is known not to cleave substrates containing the Swe β-secretase site but to readily cleave those containing the WT sequence [1,2]. Finding that cathepsin B does not have Swe β-secretase activity is corroborative but not new data, and, thus, the conclusion is a bit misleading. Moreover, reporting that cathepsin B does not cleave a substrate which it is known not to cut says nothing about cathepsin B’s role in cleaving a sequence that it does cut, the WT β-secretase site sequence. In contrast, our cathepsin B gene knockout data confirm previous enzymology data showing that cathepsin B has WT β-secretase activity in an appropriate transgenic mouse model [2,3]. I hope these observations help readers focus on the conclusion that is actually supported by the paper’s data, which is that cathepsin B lacks Swe β-secretase activity.

Greg Hook, Ph.D., JD
American Life Science Pharmaceuticals
San Diego, CA

[1] Hook VY, Kindy M, Hook G (2008) Inhibitors of cathepsin B improve memory and reduce Abeta in transgenic Alzheimer's Disease mice expressing the wild-type, but not the Swedish mutant, beta -secretase APP site. J Biol Chem 283, 7745-7753.
[2] Hook VY, Kindy M, Reinheckel T, Peters C, Hook G (2009) Genetic cathepsin B deficiency reduces beta-amyloid in transgenic mice expressing human wild-type amyloid precursor protein. Biochem Biophys Res Commun 386, 284-288.
[3] Kindy MS, Yu J, Zhu H, El-Amouri SS, Hook V, Hook GR (2012) 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. J Alzheimers Dis 29, 827-840