BACE1 Dynamics Upon Inhibition with a BACE Inhibitor and Correlation to Downstream Alzheimer's Disease Markers in Elderly Healthy Participants.
The β-site amyloid-β protein precursor (AβPP) cleaving enzyme-1 (BACE1) is the rate limiting enzyme in the generation of amyloid-β peptide (Aβ) from AβPP, one of the major pathways in Alzheimer's disease (AD) pathology. Increased BACE1 levels and activity have been reported in the brain of patients with sporadic AD. Therefore, changes of BACE1 levels in the cerebrospinal fluid (CSF) have also been investigated as a possible biomarker of the disease. We analyzed BACE1 levels in CSF of elderly healthy participants before and after chronic treatment with a BACE inhibitor (BACEi) and evaluated the correlation between BACE1 levels and downstream AD markers. Overall, BACE1 CSF levels showed strong correlations to all downstream AD markers investigated. This is the first reported finding that shows BACE1 levels in CSF were well correlated to its end product Aβ1 - 42. As previously described, BACE1 levels were strongly correlated to total-tau and phosphorylated tau levels in CSF. Generally, chronic BACE inhibition did not influence BACE1 CSF protein levels. Follow-up studies including early-stage AD pathophysiology and prodromal AD patients will help to understand the importance of measuring BACE1 routinely in daily clinical practice and AD clinical trials.
Janssen Research and Development, A Division of Janssen Pharmaceutica N.V., Beerse, Belgium.|Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
Maarten
M
Timmers
VIB Center for the Biology of Disease, VIB-Leuven, Belgium.|Center for Human Genetics, Universitaire ziekenhuizen and LIND, KU Leuven, Belgium.
Soraia
S
Barão
Janssen Research and Development, A Division of Janssen Pharmaceutica N.V., Beerse, Belgium.
Bianca
B
Van Broeck
Janssen Research and Development, A Division of Janssen Pharmaceutica N.V., Beerse, Belgium.
Ina
I
Tesseur
Janssen Research and Development LLC, La Jolla, CA, USA.
John
J
Slemmon
Janssen Research and Development, A Division of Janssen Pharmaceutica N.V., Beerse, Belgium.
Katja
K
De Waepenaert
Janssen Research and Development LLC, Raritan, NJ, USA.
Jennifer
J
Bogert
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Leslie M
LM
Shaw
Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.|Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium.
Sebastiaan
S
Engelborghs
Janssen Research and Development, A Division of Janssen Pharmaceutica N.V., Beerse, Belgium.
Dieder
D
Moechars
Janssen Research and Development, A Division of Janssen Pharmaceutica N.V., Beerse, Belgium.
Marc
M
Mercken
Janssen Research and Development, A Division of Janssen Pharmaceutica N.V., Beerse, Belgium.
Luc
L
Van Nueten
Janssen Research and Development, A Division of Janssen Pharmaceutica N.V., Beerse, Belgium.
Luc
L
Tritsmans
VIB Center for the Biology of Disease, VIB-Leuven, Belgium.|Center for Human Genetics, Universitaire ziekenhuizen and LIND, KU Leuven, Belgium.|Institute of Neurology, University College London, UK.
Bart
B
de Strooper
Janssen Research and Development, A Division of Janssen Pharmaceutica N.V., Beerse, Belgium.|Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
Johannes Rolf
JR
Streffer
D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D053327:Apolipoprotein E4 / Q000235:genetics; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D011480:Protease Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016875:tau Proteins / Q000134:cerebrospinal fluid*
D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D015415:Biomarkers; C054369:MAPT protein, human; D011480:Protease Inhibitors; D016875:tau Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
AD markers; Alzheimer’s disease; BACE-1; JNJ-54861911; β-secretase enzyme