Enzyme shreds Alzheimer’s protein

An enzyme found naturally in the brain snips apart the protein that forms the sludge called amyloid plaque that is one of the hallmarks of Alzheimer’s disease (AD), researchers have found. They said their findings in mice suggest that the protein, called Cathepsin B (CatB), is a key part of a protective mechanism that may fail in some forms of AD. Also, they said their findings suggest that drugs to enhance CatB activity could break down amyloid deposits, counteracting one of the central pathologies of AD.

Li Gan and colleagues published their findings in the September 21, 2006, issue of the journal Neuron, published by Cell Press.

Their experiments were prompted by previous studies showing that the cysteine protease CatB–an enzyme that snips apart proteins–closely associated with the amyloid-ß (Aß) protein that forms the amyloid plaques, a hallmark of AD. However, those studies had not determined whether CatB was “good” or “bad”–that is, whether it acted to produce Aß from a longer protein, called amyloid precursor protein (APP), or whether it broke down Aß.

In their experiments, Gan and colleagues determined that CatB was the latter–breaking down Aß, apparently to enable other enzymes to further degrade the protein for the cell’s protein “garbage deposal” system.

They found that knocking out the CatB gene increased plaque deposition in a mouse model of AD in which mice expressed the human form of APP. They also found that CatB tended to accumulate within amyloid plaques and that it acted to reduce Aß levels in neurons. And they found that introducing a pathological form of Aß, called Aß1-42, into neurons increased CatB in young and middle-aged mice with human APP, but not old mice. “Thus, upregulation of CatB may represent a protective mechanism that fails with aging,” wrote the researchers, and such failure may play a role in late-onset sporadic AD.

Their test tube studies showed that CatB biochemically degrades Aß by snipping one end of the protein, called the C-terminal end. What’s more, the enzyme also degrades the long strings of Aß that form amyloid plaque, they found.

Finally, they found that increasing levels of CatB in aging mice with human APP markedly reduced plaque deposits in the animals’ brains.

Gan and colleagues concluded that “our findings suggest that inhibition or loss of CatB function could interfere with its protective function and promote the development of AD, whereas overexpression of CatB could counteract Aß accumulation and aggregation. Thus, pharmacological activation of CatB could downregulate Aß1-42 assemblies through C-terminal truncation, offering an approach to the treatment of AD.”

From Cell Press


  1. The conclusion of the paper by Li Gan and colleagues (Neuron 51(6): 703-714, 2006) that cathepsin B does not have beta-secretase activity for human APP (hAPP) is misleading. Although not explicitly disclosed, the transgenic mice used in this study express hAPP containing Swedish mutations at the beta-secretase site (hAPPswe). hAPPswe is an exceedingly rare form of hAPP. The vast majority of Alzheimer’s patients express hAPP containing the wild-type beta-secretase site (hAPPwt). The altered beta-secretase site in the Swedish mutant form can change the beta-secretase activity compared to that utilized for the wild-type ß-secretase site. Thus, in agreement with our findings, the data in this paper support the very narrow conclusion that cathepsin B does not have beta-secretase activity for the rare APPswe. Unfortunately, the failure to make this point clearly in the paper has led some readers to erroneously conclude that cathepsin B has no beta-secretase activity for hAPP generally.

    In fact, cathepsin B has excellent beta-secretase activity for the wild-type beta-secretase site required for production of beta-amyloid (Abeta). Cathepsin B inhibitors reduce both Abeta production and beta-secretase activity in guinea pigs expressing APP containing the human wild-type beta secretase site, reported by Hook et al., 2007. Cathepsin B inhibitors resulted in substantial reduction of Abeta peptide levels in brain by 50%-70%. These inhibitors decreased brain levels of CTFbeta derived from APP by processing at the beta-secretase site, which indicated that the cathepsin B inhibitors reduced beta-secretase. It has been reported that cathepsin B activity in Abeta-containing secretory vesicles does not cleave the the Swedish mutant site (Hook et al., 2002). Therefore, the finding that cathepsin B is not involved in processing Swedish mutant APP, as reported by Gan et al., 2006, was to be expected. Importantly, however, results by Hook et al., 2007 show that cathepsin B remains a critical parameter for generating neurotoxic Abeta from wild-type APP that is relevant to the majority of Alzheimer’s disease patients. Thus, cathepsin B remains a critical parameter to be considered in the regulation of Abeta production in Alzheimer’s disease research.

    [1, 2]

    1. Hook, V., Kindy, M. & Hook, G. (2007) Cysteine protease inhibitors effectively reduce in vivo levels of brain beta-amyloid related to Alzheimer’s disease, Biol Chem. 388, 247-52.
    2. Hook, V. Y. H., Toneff, T., Aaron, W., Yasothornsrikul, S., Bundey, R. & Reisine, T. (2002) _-Amyloid peptide in regulated secretory vesicles of chromaffin cells: evidence for multiple cysteine proteolytic activities in distinct pathways for _-secretase activity in chromaffin vesicles, Journal of Neurochemistry. 81, 237-256.


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