Compounds that bind APP and inhibit Abeta processing in vitro suggest a novel approach to Alzheimer disease therapeutics.
Extracellular deposits of aggregated amyloid-beta (Abeta) peptides are a hallmark of Alzheimer disease; thus, inhibition of Abeta production and/or aggregation is an appealing strategy to thwart the onset and progression of this disease. The release of Abeta requires processing of the amyloid precursor protein (APP) by both beta- and gamma-secretase. Using an assay that incorporates full-length recombinant APP as a substrate for beta-secretase (BACE), we have identified a series of compounds that inhibit APP processing, but do not affect the cleavage of peptide substrates by BACE1. These molecules also inhibit the processing of APP and Abeta by BACE2 and selectively inhibit the production of Abeta(42) species by gamma-secretase in assays using CTF99. The compounds bind directly to APP, likely within the Abeta domain, and therefore, unlike previously described inhibitors of the secretase enzymes, their mechanism of action is mediated through APP. These studies demonstrate that APP binding agents can affect its processing through multiple pathways, providing proof of concept for novel strategies aimed at selectively modulating Abeta production.
Espeseth
Amy S
AS
Biological Chemistry, Medicinal Chemistry, and Automated Biotechnology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Xu
Min
M
Huang
Qian
Q
Coburn
Craig A
CA
Jones
Kristen L G
KL
Ferrer
Marc
M
Zuck
Paul D
PD
Strulovici
Berta
B
Price
Eric A
EA
Wu
Guoxin
G
Wolfe
Abigail L
AL
Lineberger
Janet E
JE
Sardana
Mohinder
M
Tugusheva
Katherine
K
Pietrak
Beth L
BL
Crouthamel
Ming-Chih
MC
Lai
Ming-Tain
MT
Dodson
Elizabeth Chen
EC
Bazzo
Renzo
R
Shi
Xiao-Ping
XP
Simon
Adam J
AJ
Li
Yueming
Y
Hazuda
Daria J
DJ
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases; D006367:HeLa Cells; D006801:Humans; D011480:Protease Inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D011499:Protein Processing, Post-Translational / Q000187:drug effects*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509284:BACE2 protein, human; C509280:BACE1 protein, human