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

The Journal of Pharmacology and Experimental Therapeutics
Yasong LuMartin Pettersson

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 separa...Continue Reading

References

Apr 10, 1992·Science·J A Hardy, G A Higgins
Jun 27, 2006·Nature Medicine·Randall J BatemanDavid M Holtzman
Jul 10, 2007·The Journal of Biological Chemistry·Lisa McConlogueSukanto Sinha
Oct 5, 2007·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Tong LiPhilip C Wong
Oct 3, 2008·Brain : a Journal of Neurology·David S KnopmanNathaniel Mercaldo
Nov 4, 2008·Biological Chemistry·Vivian HookGregory Hook
Apr 11, 2009·Annals of Neurology·Randall J BatemanDavid M Holtzman
May 14, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Jacquelynn J CookRandall J Bateman
Dec 15, 2010·Science·Kwasi G MawuenyegaRandall J Bateman
Jan 13, 2011·Expert Opinion on Investigational Drugs·Bruno P ImbimboAlberto Pilotto
Jan 15, 2011·Expert Opinion on Therapeutic Patents·Martin PetterssonDouglas S Johnson
Jan 1, 2009·Progress in Medicinal Chemistry·Jeffrey S Albert
May 27, 2011·Science Translational Medicine·Jasvinder K AtwalRyan J Watts
Aug 20, 2011·Nature Reviews. Drug Discovery·Eric KarranBart De Strooper
Nov 18, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Patrick C MayJames E Audia

❮ Previous
Next ❯

Citations

Oct 11, 2012·The Journal of Biological Chemistry·Fredrik JeppssonJohanna Fälting
Jul 18, 2014·Alzheimer's Research & Therapy·Jeremy H Toyn, Michael K Ahlijanian
Nov 8, 2014·Science Translational Medicine·Y Joy YuRyan J Watts
Apr 26, 2013·Biochemistry·Christina J CrumpYue-Ming Li
Jan 31, 2016·The Journal of Pharmacology and Experimental Therapeutics·Eline M T van MaanenMeindert Danhof
May 18, 2016·The Journal of Pharmacology and Experimental Therapeutics·Jeremy H ToynMichael K Ahlijanian
Dec 21, 2016·Journal of Medicinal Chemistry·Christopher R ButlerMichael A Brodney
Mar 23, 2017·Cold Spring Harbor Perspectives in Medicine·Douglas S JohnsonPeter H St George-Hyslop
Mar 12, 2013·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Anders LindgrenTjerk Bueters
Apr 16, 2013·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Xingrong LiuCornelis E C A Hop
Jun 15, 2016·CPT: Pharmacometrics & Systems Pharmacology·J S KanodiaS Joseph
Feb 20, 2015·Journal of Medicinal Chemistry·Christopher R ButlerBrian T O'Neill

❮ Previous
Next ❯

Related Concepts

Related Feeds

Alzheimer's Disease: APP

Amyloid precursor protein (APP) proteolysis is critical for the development of Alzheimer's disease, a neurodegenerative disease associated with accumulation of amyloid plaques in the brain. Here is the latest research on APP and Alzheimer's disease.

Alzheimer's Disease: Amyloid Beta

Alzheimer's disease is a neurodegenerative disease associated with the accumulation of amyloid plaques in the brain; these plaques are comprised of amyloid beta deposits. Here is the latest research in this field.

CSF & Lymphatic System

This feed focuses on Cerebral Spinal Fluid (CSF) and the lymphatic system. Discover the latest papers using imaging techniques to track CSF outflow into the lymphatic system in animal models.