Conversion of Aβ43 to Aβ40 by the successive action of angiotensin-converting enzyme 2 and angiotensin-converting enzyme.
The longer and neurotoxic species of amyloid-β protein (Aβ), Aβ42 and Aβ43, contribute to Aβ accumulation in Alzheimer's disease (AD) pathogenesis and are considered to be the primary cause of the disease. In contrast, the predominant secreted form of Aβ, Aβ40, inhibits amyloid deposition and may have neuroprotective effects. We have reported that angiotensin-converting enzyme (ACE) converts Aβ42 to Aβ40 and that Aβ43 is the earliest-depositing Aβ species in the amyloid precursor protein transgenic mouse brain. Here we found that Aβ43 can be converted to Aβ42 and to Aβ40 in mouse brain lysate. We further identified the brain Aβ43-to-Aβ42-converting enzyme as ACE2. The purified human ACE2 converted Aβ43 to Aβ42, and this activity was inhibited by a specific ACE2 inhibitor, DX600. Notably, the combination of ACE2 and ACE could convert Aβ43 to Aβ40. Our results indicate that the longer, neurotoxic forms of Aβ can be converted to the shorter, less toxic or neuroprotective forms of Aβ by ACE2 and ACE. Moreover, we found that ACE2 activity showed a tendency to decrease in the serum of AD patients compared with normal controls, suggesting an association between lower ACE2 activity and AD. Thus, maintaining brain ACE2 and ACE activities may be important for preventing brain amyloid neurotoxicity and deposition in Alzheimer's disease.
Department of Neuroscience, School of Pharmacy, Iwate Medical University, Yahaba, Japan.
Shuyu
S
Liu
Junjun
J
Liu
Yukie
Y
Miura
Chiaki
C
Tanabe
Tomoji
T
Maeda
Yasuo
Y
Terayama
Anthony J
AJ
Turner
Kun
K
Zou
Hiroto
H
Komano
D000544:Alzheimer Disease / Q000097:blood; D016229:Amyloid beta-Peptides / Q000187:drug effects / Q000378:metabolism*; D000085962:Angiotensin-Converting Enzyme 2; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D010446:Peptide Fragments / Q000187:drug effects / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism* / Q000494:pharmacology; D044967:Serum / Q000187:drug effects / Q000378:metabolism
D016229:Amyloid beta-Peptides; D000806:Angiotensin-Converting Enzyme Inhibitors; C556151:DX600 peptide; D010446:Peptide Fragments; D010455:Peptides; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C098994:amyloid beta-protein (1-43); D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2
Alzheimer's disease; amyloid-β protein; angiotensin-converting enzyme; angiotensin-converting enzyme 2