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Cerebrospinal fluid amyloid-β (Aβ) as an effect biomarker for brain Aβ lowering verified by quantitative preclinical analyses
Journal article   Peer reviewed

Cerebrospinal fluid amyloid-β (Aβ) as an effect biomarker for brain Aβ lowering verified by quantitative preclinical analyses

Yasong Lu, Brian T O'Neill, David Riddell, Eva Hajos-Korcsok, Kelly Bales, Kathleen M Wood, Charles E Nolan, Ashley E Robshaw, Liming Zhang, Louis Leung, …
The Journal of pharmacology and experimental therapeutics, Vol.342(2), pp.366-375
08/2012
DOI: 10.1124/jpet.112.192625
PMID: 22562771
url
https://www.ncbi.nlm.nih.gov/pmc/articles/11047765View
Open Access

Abstract

Reducing the generation of amyloid-β (Aβ) in the brain via inhibition of β-secretase or inhibition/modulation of γ-secretase has been pursued as a potential disease-modifying treatment for Alzheimer's disease. For the discovery and development of β-secretase inhibitors (BACEi), γ-secretase inhibitors (GSI), and γ-secretase modulators (GSM), Aβ in cerebrospinal fluid (CSF) has been presumed to be an effect biomarker for Aβ lowering in the brain. However, this presumption is challenged by the lack of quantitative understanding of the relationship between brain and CSF Aβ lowering. In this study, we strived to elucidate how the intrinsic pharmacokinetic (PK)/pharmacodynamic (PD) relationship for CSF Aβ lowering is related to that for brain Aβ through quantitative modeling of preclinical data for numerous BACEi, GSI, and GSM across multiple species. Our results indicate that the intrinsic PK/PD relationship in CSF is predictive of that in brain, at least in the postulated pharmacologically relevant range, with excellent consistency across mechanisms and species. As such, the validity of CSF Aβ as an effect biomarker for brain Aβ lowering is confirmed preclinically. Meanwhile, we have been able to reproduce the dose-dependent separation between brain and CSF effect profiles using simulations. We further discuss the implications of our findings to drug discovery and development with regard to preclinical PK/PD characterization and clinical prediction of Aβ lowering in the brain.
 Biomarkers - metabolism Guinea Pigs Alzheimer Disease - drug therapy Rats Male Mice, 129 Strain Alzheimer Disease - cerebrospinal fluid Rats, Sprague-Dawley Amyloid Precursor Protein Secretases - cerebrospinal fluid Brain - metabolism Protease Inhibitors - pharmacology Amyloid Precursor Protein Secretases - metabolism Animals Cerebrospinal Fluid - chemistry Alzheimer Disease - metabolism Amyloid beta-Peptides - metabolism Amyloid beta-Peptides - cerebrospinal fluid Mice Amyloid Precursor Protein Secretases - antagonists & inhibitors Biomarkers - cerebrospinal fluid

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