Felbor U, Kessler B, Mothes W, Goebel HH, Ploegh HL, Bronson RT, Olsen BR.
Neuronal loss and brain atrophy in mice lacking cathepsins B and L.
Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):7883-8.
PubMed.
While there may be some evidence that cathepsins might share some BACE1-like properties, our BACE1 KO neurons/mice clearly demonstrated that it is unlikely there exist other BACE1 homologues as far as processing AbPP is concerned. Moreover, there is no evidence that cathepsin B/L are involved in AbPP processing. So I don't think that the information in this paper has any relevance for AD.
I have to take issue on two accounts with Phil Wong's assessment of the Felbor et al. study. First, relevance to Alzheimer’s disease cannot be judged simply in terms of a protease's effect on AβPP processing. Neurodegeneration, the likely basis for memory loss in AD, almost certainly involves proteases that are not AβPP secretases and may be regulated by disease-related factors that are independent of AβPP and its metabolites. Growing evidence implicates the lysosomal system, including aging-related cysteine protease dysfunction in the pathogenesis of Alzheimer's disease (reviewed in J. Alzheimers Dis., 2001) and aging (J Neurochem., 2002).
Second, even in evaluating relevance to AβPP processing in AD, a direct action of a protease on AβPP should be regarded as only one of several ways in which proteases may be influential. Other ways include modifying AβPP trafficking and modulating the activity of AβPP secretases directly or indirectly. For example, calpains are not considered AβPP secretases, but their activity regulates AβPP delivery to the cell surface and strongly modulates Aβ generation (J Biol Chem., 2002). Overexpression of the cation-dependent mannose-6-phosphate receptor, as occurs in AD brain, increases delivery of a limited set of mannosylated cathepsins to early endosomes, promoting Aβ production in the endocytic pathway (J Biol Chem., 2002;277:5299-307).
Unless or until the exclusive role of Aβ in the death of neurons in AD is conclusively established and the mediating proteases are defined, any model of neurodegeneration involving proteases known to be altered in aging and Alzheimer's disease has the potential to inform us about disease pathogenesis.
References:
Nixon RA, Mathews PM, Cataldo AM.
The neuronal endosomal-lysosomal system in Alzheimer's disease.
J Alzheimers Dis. 2001 Feb;3(1):97-107.
PubMed.
Bahr BA, Bendiske J.
The neuropathogenic contributions of lysosomal dysfunction.
J Neurochem. 2002 Nov;83(3):481-9.
PubMed.
Mathews PM, Jiang Y, Schmidt SD, Grbovic OM, Mercken M, Nixon RA.
Calpain activity regulates the cell surface distribution of amyloid precursor protein. Inhibition of calpains enhances endosomal generation of beta-cleaved C-terminal APP fragments.
J Biol Chem. 2002 Sep 27;277(39):36415-24.
PubMed.
Comments
Johns Hopkins
While there may be some evidence that cathepsins might share some BACE1-like properties, our BACE1 KO neurons/mice clearly demonstrated that it is unlikely there exist other BACE1 homologues as far as processing AbPP is concerned. Moreover, there is no evidence that cathepsin B/L are involved in AbPP processing. So I don't think that the information in this paper has any relevance for AD.
View all comments by Philip WongNew York University School of Medicine/Nathan Kline Institute
I have to take issue on two accounts with Phil Wong's assessment of the Felbor et al. study. First, relevance to Alzheimer’s disease cannot be judged simply in terms of a protease's effect on AβPP processing. Neurodegeneration, the likely basis for memory loss in AD, almost certainly involves proteases that are not AβPP secretases and may be regulated by disease-related factors that are independent of AβPP and its metabolites. Growing evidence implicates the lysosomal system, including aging-related cysteine protease dysfunction in the pathogenesis of Alzheimer's disease (reviewed in J. Alzheimers Dis., 2001) and aging (J Neurochem., 2002).
Second, even in evaluating relevance to AβPP processing in AD, a direct action of a protease on AβPP should be regarded as only one of several ways in which proteases may be influential. Other ways include modifying AβPP trafficking and modulating the activity of AβPP secretases directly or indirectly. For example, calpains are not considered AβPP secretases, but their activity regulates AβPP delivery to the cell surface and strongly modulates Aβ generation (J Biol Chem., 2002). Overexpression of the cation-dependent mannose-6-phosphate receptor, as occurs in AD brain, increases delivery of a limited set of mannosylated cathepsins to early endosomes, promoting Aβ production in the endocytic pathway (J Biol Chem., 2002;277:5299-307).
Unless or until the exclusive role of Aβ in the death of neurons in AD is conclusively established and the mediating proteases are defined, any model of neurodegeneration involving proteases known to be altered in aging and Alzheimer's disease has the potential to inform us about disease pathogenesis.
References:
Nixon RA, Mathews PM, Cataldo AM. The neuronal endosomal-lysosomal system in Alzheimer's disease. J Alzheimers Dis. 2001 Feb;3(1):97-107. PubMed.
Bahr BA, Bendiske J. The neuropathogenic contributions of lysosomal dysfunction. J Neurochem. 2002 Nov;83(3):481-9. PubMed.
Mathews PM, Jiang Y, Schmidt SD, Grbovic OM, Mercken M, Nixon RA. Calpain activity regulates the cell surface distribution of amyloid precursor protein. Inhibition of calpains enhances endosomal generation of beta-cleaved C-terminal APP fragments. J Biol Chem. 2002 Sep 27;277(39):36415-24. PubMed.
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