The amyloid-beta rise and gamma-secretase inhibitor potency depend on the level of substrate expression.
The amyloid-beta (Abeta) peptide, which likely plays a key role in Alzheimer disease, is derived from the amyloid-beta precursor protein (APP) through consecutive proteolytic cleavages by beta-site APP-cleaving enzyme and gamma-secretase. Unexpectedly gamma-secretase inhibitors can increase the secretion of Abeta peptides under some circumstances. This "Abeta rise" phenomenon, the same inhibitor causing an increase in Abeta at low concentrations but inhibition at higher concentrations, has been widely observed. Here we show that the Abeta rise depends on the beta-secretase-derived C-terminal fragment of APP (betaCTF) or C99 levels with low levels causing rises. In contrast, the N-terminally truncated form of Abeta, known as "p3," formed by alpha-secretase cleavage, did not exhibit a rise. In addition to the Abeta rise, low betaCTF or C99 expression decreased gamma-secretase inhibitor potency. This "potency shift" may be explained by the relatively high enzyme to substrate ratio under conditions of low substrate because increased concentrations of inhibitor would be necessary to affect substrate turnover. Consistent with this hypothesis, gamma-secretase inhibitor radioligand occupancy studies showed that a high level of occupancy was correlated with inhibition of Abeta under conditions of low substrate expression. The Abeta rise was also observed in rat brain after dosing with the gamma-secretase inhibitor BMS-299897. The Abeta rise and potency shift are therefore relevant factors in the development of gamma-secretase inhibitors and can be evaluated using appropriate choices of animal and cell culture models. Hypothetical mechanisms for the Abeta rise, including the "incomplete processing" and endocytic models, are discussed.
Burton
Catherine R
CR
Bristol-Myers Squibb Research and Development, Wallingford, Connecticut 06492, USA.
Meredith
Jere E
JE
Barten
Donna M
DM
Goldstein
Margi E
ME
Krause
Carol M
CM
Kieras
Cathy J
CJ
Sisk
Lisa
L
Iben
Lawrence G
LG
Polson
Craig
C
Thompson
Mark W
MW
Lin
Xu-Alan
XA
Corsa
Jason
J
Fiedler
Tracey
T
Pierdomenico
Maria
M
Cao
Yang
Y
Roach
Arthur H
AH
Cantone
Joseph L
JL
Ford
Michael J
MJ
Drexler
Dieter M
DM
Olson
Richard E
RE
Yang
Michael G
MG
Bergstrom
Carl P
CP
McElhone
Kate E
KE
Bronson
Joanne J
JJ
Macor
John E
JE
Blat
Yuval
Y
Grafstrom
Robert H
RH
Stern
Andrew M
AM
Seiffert
Dietmar A
DA
Zaczek
Robert
R
Albright
Charles F
CF
Toyn
Jeremy H
JH
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002087:Butyrates / Q000494:pharmacology; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000494:pharmacology; D051379:Mice; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D013379:Substrate Specificity
C497115:4-(2-((1R)-1-(((4-chlorophenyl)sulfonyl)-2,5-difluoroanilino)ethyl)-5-fluorophenyl)butanoic acid; D016229:Amyloid beta-Peptides; D002087:Butyrates; D004791:Enzyme Inhibitors; D006846:Hydrocarbons, Halogenated; D053829:Amyloid Precursor Protein Secretases