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

作者：Timmers Maarten; Barao Soraia; Van Broeck Bianca; Tesseur Ina; Slemmon John; De Waepenaert Katja; Bogert Jennifer; Shaw Leslie M; Engelborghs Sebastiaan; Moechars Dieder; Mercken Marc; Van Nueten Luc; Tritsmans Luc; de Strooper Bart; Streffer Johannes Rolf^*

来源：Journal of Alzheimer's Disease, 2017, 56(4): 1437-1449.

DOI：10.3233/JAD-160829

• AD markers
• Alzheimer's disease
• BACE-1
• beta-secretase enzyme
• JNJ-54861911

The beta-site amyloid-beta protein precursor (A beta PP) cleaving enzyme-1 (BACE1) is the rate limiting enzyme in the generation of amyloid-beta peptide (A beta) from A beta PP, 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 A beta(1-42). 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.

• 出版日期2017