Γ-secretase modulators do not induce Aβ-rebound and accumulation of β-C-terminal fragment.

Abstract

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.

• Authors: Ting Li, Yunhong Huang, Shiyi Jin, Liang Ye, Na Rong, Xiujuan Yang, Yu Ding, Ziqiang Cheng, Jinqiang Zhang, Zehong Wan, David C Harrison, Ishrut Hussain, Adrian Hall, Daniel Hong Seng Lee, Lit-Fui Lau, Yasuji Matsuoka
• Journal: Journal of neurochemistry (J Neurochem) Vol. 121 Issue 2 Pg. 277-86 (Apr 2012) ISSN: 1471-4159 [Electronic] England
• PMID: 22035227 (Publication Type: Journal Article)
• Copyright: © 2011 GlaxoSmithKline. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

Chemical References

• Amyloid beta-Peptides
• Azepines
• Enzyme Inhibitors
• 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
• Peptide Fragments
• Receptors, Notch
• Amyloid Precursor Protein Secretases
• Alanine

Topics

• Alanine (analogs & derivatives, pharmacokinetics, pharmacology)
• Amyloid Precursor Protein Secretases (antagonists & inhibitors, drug effects)
• Amyloid beta-Peptides (biosynthesis, genetics)
• Animals
• Area Under Curve
• Azepines (pharmacokinetics, pharmacology)
• Cell Line
• Cells, Cultured
• Chromatography, High Pressure Liquid
• Enzyme Inhibitors (pharmacokinetics, pharmacology)
• Humans
• Male
• Mice
• Mice, Transgenic
• Neurons (pathology)
• Peptide Fragments (metabolism)
• Plaque, Amyloid (pathology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Notch (drug effects)
• Signal Transduction (drug effects)