Γ-secretase modulators do not induce Aβ-rebound and accumulation of β-C-terminal fragment.
γ-secretase inhibitors (GSIs) have been developed to reduce amyloid-β (Aβ) production for the treatment of Alzheimer's disease by inhibiting the cleavage of amyloid precursor protein (APP). However, cross-inhibitory activity on the processing of Notch can cause adverse reactions. To avoid these undesirable effects, γ-secretase modulators (GSMs) are being developed to selectively reduce toxic Aβ production without perturbing Notch signaling. As it is also known that GSIs can cause a paradoxical increase of plasma Aβ over the baseline after a transient reduction (known as Aβ-rebound), we asked if GSMs would cause a similar rebound and what the potential mechanism might be. Our studies were performed with one GSI (LY-450139) and two chemically distinct GSMs. Although LY-450139 caused Aβ-rebound as expected in rat plasma, the two GSMs did not. Inhibition of APP processing by LY-450139 induced an accumulation of γ-secretase substrates, α- and β-C-terminal fragments of APP, but neither GSM caused such an accumulation. In conclusion, we discover that GSMs, unlike GSIs, do not cause Aβ-rebound, possibly because of the lack of accumulation of β-C-terminal fragments. GSMs may be superior to GSIs in the treatment of Alzheimer's disease not only by sparing Notch signaling but also by avoiding Aβ-rebound.
Neurodegeneration Research, R&D China, GlaxoSmithKline, Shanghai, China.
Ting
T
Li
Yunhong
Y
Huang
Shiyi
S
Jin
Liang
L
Ye
Na
N
Rong
Xiujuan
X
Yang
Yu
Y
Ding
Ziqiang
Z
Cheng
Jinqiang
J
Zhang
Zehong
Z
Wan
David C
DC
Harrison
Ishrut
I
Hussain
Adrian
A
Hall
Daniel Hong Seng
DH
Lee
Lit-Fui
LF
Lau
Yasuji
Y
Matsuoka
D000409:Alanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000187:drug effects*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D019540:Area Under Curve; D001381:Azepines / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051880:Receptors, Notch / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
D016229:Amyloid beta-Peptides; D001381:Azepines; D004791:Enzyme Inhibitors; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; D010446:Peptide Fragments; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; D000409:Alanine