BACE1 inhibition reduces endogenous Abeta and alters APP processing in wild-type mice.
Accumulation of amyloid beta peptide (Abeta) in brain is a hallmark of Alzheimer's disease (AD). Inhibition of beta-site amyloid precursor protein (APP)-cleaving enzyme-1 (BACE1), the enzyme that initiates Abeta production, and other Abeta-lowering strategies are commonly tested in transgenic mice overexpressing mutant APP. However, sporadic AD cases, which represent the majority of AD patients, are free from the mutation and do not necessarily have overproduction of APP. In addition, the commonly used Swedish mutant APP alters APP cleavage. Therefore, testing Abeta-lowering strategies in transgenic mice may not be optimal. In this study, we investigated the impact of BACE1 inhibition in non-transgenic mice with physiologically relevant APP expression. Existing Abeta ELISAs are either relatively insensitive to mouse Abeta or not specific to full-length Abeta. A newly developed ELISA detected a significant reduction of full-length soluble Abeta 1-40 in mice with the BACE1 homozygous gene deletion or BACE1 inhibitor treatment, while the level of x-40 Abeta was moderately reduced due to detection of non-full-length Abeta and compensatory activation of alpha-secretase. These results confirmed the feasibility of Abeta reduction through BACE1 inhibition under physiological conditions. Studies using our new ELISA in non-transgenic mice provide more accurate evaluation of Abeta-reducing strategies than was previously feasible.
Nishitomi
Kouhei
K
Pain & Neurology, Discovery Research Laboratories, Shionogi Co. Ltd, Shiga, Japan.
Sakaguchi
Gaku
G
Horikoshi
Yuko
Y
Gray
Audrey J
AJ
Maeda
Masahiro
M
Hirata-Fukae
Chiho
C
Becker
Amanda G
AG
Hosono
Motoko
M
Sakaguchi
Isako
I
Minami
S Sakura
SS
Nakajima
Yoshihiro
Y
Li
Hui-Fang
HF
Takeyama
Chie
C
Kihara
Tsuyoshi
T
Ota
Akinobu
A
Wong
Philip C
PC
Aisen
Paul S
PS
Kato
Akira
A
Kinoshita
Noriaki
N
Matsuoka
Yasuji
Y
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D015153:Blotting, Western / Q000379:methods; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000187:drug effects*; D009474:Neurons / Q000378:metabolism; D014280:Triglycerides; D015854:Up-Regulation / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000187:drug effects
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D014280:Triglycerides; D005680:gamma-Aminobutyric Acid; C057077:1,2-dilinolenoyl-3-(4-aminobutyryl)propane-1,2,3-triol; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse