BACE1 Dynamics Upon Inhibition with a BACE Inhibitor and Correlation to Downstream Alzheimer's Disease Markers in Elderly Healthy Participants.

Autor:	Timmers M; 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., Barão S; VIB Center for the Biology of Disease, VIB-Leuven, Belgium.; Center for Human Genetics, Universitaire ziekenhuizen and LIND, KU Leuven, Belgium., Van Broeck B; Janssen Research and Development, A Division of Janssen Pharmaceutica N.V., Beerse, Belgium., Tesseur I; Janssen Research and Development, A Division of Janssen Pharmaceutica N.V., Beerse, Belgium., Slemmon J; Janssen Research and Development LLC, La Jolla, CA, USA., De Waepenaert K; Janssen Research and Development, A Division of Janssen Pharmaceutica N.V., Beerse, Belgium., Bogert J; Janssen Research and Development LLC, Raritan, NJ, USA., Shaw LM; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Engelborghs S; 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., Moechars D; Janssen Research and Development, A Division of Janssen Pharmaceutica N.V., Beerse, Belgium., Mercken M; Janssen Research and Development, A Division of Janssen Pharmaceutica N.V., Beerse, Belgium., Van Nueten L; Janssen Research and Development, A Division of Janssen Pharmaceutica N.V., Beerse, Belgium., Tritsmans L; Janssen Research and Development, A Division of Janssen Pharmaceutica N.V., Beerse, Belgium., de Strooper B; 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., Streffer JR; 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.
Jazyk:	angličtina
Zdroj:	Journal of Alzheimer's disease : JAD [J Alzheimers Dis] 2017; Vol. 56 (4), pp. 1437-1449.
DOI:	10.3233/JAD-160829
Abstrakt:	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.
Databáze:	MEDLINE
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