title: 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.
abstract: Pyroglutamate amyloid-β peptides (pGlu-Aβ) are particularly pernicious forms of amyloid-β peptides (Aβ) present in Alzheimer's disease (AD) brains. pGlu-Aβ peptides are N-terminally truncated forms of full-length Aβ peptides (flAβ(1-40/42)) in which the N-terminal glutamate is cyclized to pyroglutamate to generate pGlu-Aβ(3-40/42). β-secretase cleavage of amyloid-β precursor protein (AβPP) produces flAβ(1-40/42), but it is not yet known whether the β-secretase BACE1 or the alternative β-secretase cathepsin B (CatB) participate in the production of pGlu-Aβ. Therefore, this study examined the effects of gene knockout of these proteases on brain pGlu-Aβ levels in transgenic AβPPLon mice, which express AβPP isoform 695 and have the wild-type (wt) β-secretase activity found in most AD patients. Knockout or overexpression of the CatB gene reduced or increased, respectively, pGlu-Aβ(3-40/42), flAβ(1-40/42), and pGlu-Aβ plaque load, but knockout of the BACE1 gene had no effect on those parameters in the transgenic mice. Treatment of AβPPLon mice with E64d, a cysteine protease inhibitor of CatB, also reduced brain pGlu-Aβ(3-42), flAβ(1-40/42), and pGlu-Aβ plaque load. Treatment of neuronal-like chromaffin cells with CA074Me, an inhibitor of CatB, resulted in reduced levels of pGlu-Aβ(3-40) released from the activity-dependent, regulated secretory pathway. Moreover, CatB knockout and E64d treatment has been previously shown to improve memory deficits in the AβPPLon mice. These data illustrate the role of CatB in producing pGlu-Aβ and flAβ that participate as key factors in the development of AD. The advantages of CatB inhibitors, especially E64d and its derivatives, as alternatives to BACE1 inhibitors in treating AD patients are discussed.
authors.affiliation: American Life Science Pharmaceuticals, La Jolla, CA, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Hook
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA Ralph H. Johnson VA Medical Center, Charleston, SC, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Yu
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, Departments of Neurosciences and Pharmacology, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Toneff
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA Ralph H. Johnson VA Medical Center, Charleston, SC, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Kindy
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, Departments of Neurosciences and Pharmacology, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Vivian
authors.initials: V
authors.lastname: Hook
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology*; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000187:drug effects / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004151:Dipeptides / Q000494:pharmacology; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D011761:Pyrrolidonecarboxylic Acid / Q000032:analysis*
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C400541:CA 074 methyl ester; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D002401:Cathepsin B; C533915:Ctsb protein, mouse; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D007930:Leucine; C108192:aloxistatin; D011761:Pyrrolidonecarboxylic Acid
keywords: AβPP; BACE1; Pyroglutamate amyloid-β; cathepsin B; cysteine protease; inhibitor; protease; secretion; transgenic AD mice