title: Aβ43 is the earliest-depositing Aβ species in APP transgenic mouse brain and is converted to Aβ41 by two active domains of ACE.
abstract: Amyloid-β protein (Aβ) varies in length at its carboxyl terminus. The longer Aβ species, Aβ43 and Aβ42, are highly amyloidogenic and deposit more frequently than Aβ40 in the brain of Alzheimer disease (AD) patients. However, the characterization of Aβ43 deposition in the brain and the relationship between Aβ43 and Aβ42 or Aβ40 remain unclear. We provide evidence that Aβ43 deposition appears earlier than Aβ42 and Aβ40 deposition in the brain of mutant amyloid precursor protein transgenic (APPtg) mice, suggesting that Aβ43 is the earliest-depositing species. In addition, we found increased Aβ43 levels and Aβ43/Aβ42 ratios in the serum of AD patients, suggesting their use as diagnostic blood biomarkers for AD. We further show that angiotensin-converting enzyme (ACE) converts Aβ43 to Aβ41. Notably, this Aβ43-to-Aβ41 converting activity requires two active domains of ACE. Inhibition of ACE activity significantly enhanced Aβ43 deposition in APPtg mouse brain. Our results suggest that Aβ43 is the earliest-depositing species in brain parenchyma and that Aβ43 may trigger later Aβ42 and Aβ40 deposition or may be converted to Aβ42 and Aβ40 plaques. Activities of both ACE domains may be important for reducing Aβ43 levels in serum and reducing brain Aβ43 deposition.
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, Yahaba, Japan. kunzou@iwate-med.ac.jp
authors.forename: Kun
authors.initials: K
authors.lastname: Zou
authors.forename: Junjun
authors.initials: J
authors.lastname: Liu
authors.forename: Atsushi
authors.initials: A
authors.lastname: Watanabe
authors.forename: Saeko
authors.initials: S
authors.lastname: Hiraga
authors.forename: Shuyu
authors.initials: S
authors.lastname: Liu
authors.forename: Chiaki
authors.initials: C
authors.lastname: Tanabe
authors.forename: Tomoji
authors.initials: T
authors.lastname: Maeda
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terayama
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takahashi
authors.forename: Makoto
authors.initials: M
authors.lastname: Michikawa
authors.forename: Hiroto
authors.initials: H
authors.lastname: Komano
mesh_terms: D000368:Aged; D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000097:blood / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001921:Brain / Q000378:metabolism*; D002216:Captopril / Q000494:pharmacology; D016022:Case-Control Studies; D018450:Disease Progression; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010446:Peptide Fragments / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000502:physiology; D053763:Presenilins / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000806:Angiotensin-Converting Enzyme Inhibitors; D015415:Biomarkers; D010446:Peptide Fragments; D053763:Presenilins; C078592:amyloid beta-protein (1-40); C497285:amyloid beta-protein (1-41); C098994:amyloid beta-protein (1-43); D002216:Captopril; D007703:Peptidyl-Dipeptidase A