title: Cerebrospinal fluid β-Amyloid turnover in the mouse, dog, monkey and human evaluated by systematic quantitative analyses.
abstract: BACKGROUND
  Reducing brain β-amyloid (Aβ) via inhibition of β-secretase, or inhibition/modulation of γ-secretase, has been widely pursued as a potential disease-modifying treatment for Alzheimer's disease. Compounds that act through these mechanisms have been screened and characterized with Aβ lowering in the brain and/or cerebrospinal fluid (CSF) as the primary pharmacological end point. Interpretation and translation of the pharmacokinetic (PK)/pharmacodynamic (PD) relationship for these compounds is complicated by the relatively slow Aβ turnover process in these compartments.
  
  
  OBJECTIVE
  To understand Aβ turnover kinetics in preclinical species and humans.
  
  
  METHODS
  We collected CSF Aβ dynamic data after β- or γ-secretase inhibitor treatment from in-house experiments and the public domain, and analyzed the data using PK/PD modeling to obtain CSF Aβ turnover rates (kout) in the mouse, dog, monkey and human.
  
  
  RESULTS
  The kout for CSF Aβ40 follows allometry (kout = 0.395 × body weight(-0.351)). The kout for CSF Aβ40 is approximately 2-fold higher than the turnover of CSF in rodents, but in higher species, the two are comparable.
  
  
  CONCLUSIONS
  The turnover of CSF Aβ40 was systematically examined, for the first time, in multiple species through quantitative modeling of multiple data sets. Our result suggests that the clearance mechanisms for CSF Aβ in rodents may be different from those in the higher species. The understanding of Aβ turnover has considerable implications for the discovery and development of Aβ-lowering therapeutics, as illustrated from the perspectives of preclinical PK/PD characterization and preclinical-to-clinical translation.
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Groton, CT 06340, USA. Yasong.Lu @ pfizer.com
authors.forename: Yasong
authors.initials: Y
authors.lastname: Lu
authors.forename: Hugh A
authors.initials: HA
authors.lastname: Barton
authors.forename: Louis
authors.initials: L
authors.lastname: Leung
authors.forename: Liming
authors.initials: L
authors.lastname: Zhang
authors.forename: Eva
authors.initials: E
authors.lastname: Hajos-Korcsok
authors.forename: Charles E
authors.initials: CE
authors.lastname: Nolan
authors.forename: Jianhua
authors.initials: J
authors.lastname: Liu
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Becker
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Wood
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Robshaw
authors.forename: Christine K
authors.initials: CK
authors.lastname: Taylor
authors.forename: Brian T
authors.initials: BT
authors.lastname: O'Neill
authors.forename: Michael A
authors.initials: MA
authors.lastname: Brodney
authors.forename: David
authors.initials: D
authors.lastname: Riddell
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D016229:Amyloid beta-Peptides / Q000097:blood / Q000134:cerebrospinal fluid*; D000818:Animals; D004285:Dogs; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013843:Thiazines / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; C554092:BMS 708163; C569204:LY2811376; D009842:Oligopeptides; D010069:Oxadiazoles; D011743:Pyrimidines; D013449:Sulfonamides; D013843:Thiazines; C523462:benzyloxycarbonyl-leucyl-leucyl-norleucinal; D053829:Amyloid Precursor Protein Secretases