Zhang Z, Song M, Liu X, Su Kang S, Duong DM, Seyfried NT, Cao X, Cheng L, Sun YE, Ping Yu S, Jia J, Levey AI, Ye K. Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer's disease. Nat Commun. 2015 Nov 9;6:8762. PubMed.
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Zhang et al. nicely show that amyloid precursor protein (APP) is processed at new δ-secretase sites by asparagine endoprotease (AEP) using AEP gene knockout (AEP KO) mice expressing human APP containing the Swedish mutant β-secretase site sequence (APPSwe). The AEP KO APPSwe mice have lower brain Aβ levels and reduced memory deficits relative to their APPSwe counterparts, which express normal levels of AEP. The authors conclude that AEP may be a new drug target for AD. The paper thus adds to the growing list of proteases, which cleave APP, that affect neurotoxic APP fragment production and are potential AD therapeutic targets.
The AEP KO may have different effects on Aβ in transgenic mice expressing APP containing the wild-type β-secretase site sequence (APPwt) than in APPSwe mice. This is because AEP KO increases cathepsin B levels and activity relative to AEP-sufficient mice (Miller et al., 2011; Shirahama-Noda et al., 2003) and cathepsin B overexpression raises brain Aβ1-40/42 and pyroglutamate Aβ-3-40/42 levels in transgenic mice expressing APPwt (Hook et al., 2014). Further, cathepsin B KO reduces Aβ peptide levels in mice expressing APPwt but not in mice expressing APPSwe (Kindy et al., 2012). Thus, the AEP KO increases levels of cathepsin B that may increase Aβ in APPwt, but not in APPSwe mice, consistent with the results of Zhang et al.
While AEP and cathepsin B are both cysteine proteases, they are structurally very different and thus different compounds may inhibit each. For example, the compound E64, which is a potent cathepsin B inhibitor, does not inhibit AEP (Chen et al., 1997). Thus, AEP and cathepsin B inhibitors are likely to be different compounds even though both are cysteine proteases.
References:
Miller G, Matthews SP, Reinheckel T, Fleming S, Watts C. Asparagine endopeptidase is required for normal kidney physiology and homeostasis. FASEB J. 2011 May;25(5):1606-17. Epub 2011 Feb 3 PubMed.
Shirahama-Noda K, Yamamoto A, Sugihara K, Hashimoto N, Asano M, Nishimura M, Hara-Nishimura I. Biosynthetic processing of cathepsins and lysosomal degradation are abolished in asparaginyl endopeptidase-deficient mice. J Biol Chem. 2003 Aug 29;278(35):33194-9. Epub 2003 May 29 PubMed.
Hook G, Yu J, Toneff T, Kindy M, Hook V. Brain pyroglutamate amyloid-β is produced by cathepsin B and is reduced by the cysteine protease inhibitor E64d, representing a potential Alzheimer's disease therapeutic. J Alzheimers Dis. 2014;41(1):129-49. PubMed.
Kindy MS, Yu J, Zhu H, El-Amouri SS, Hook V, Hook GR. 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. 2012;29(4):827-40. PubMed.
Chen JM, Dando PM, Rawlings ND, Brown MA, Young NE, Stevens RA, Hewitt E, Watts C, Barrett AJ. Cloning, isolation, and characterization of mammalian legumain, an asparaginyl endopeptidase. J Biol Chem. 1997 Mar 21;272(12):8090-8. PubMed.
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