title: Quantitative assessment of Aβ peptide in brain, cerebrospinal fluid and plasma following oral administration of γ-secretase inhibitor MRK-560 in rats.
abstract: The β-amyloid peptides (Aβ) are thought to play a critical role in the pathophysiology of Alzheimer's disease. One therapeutic strategy aimed to reduce or eliminate the production of Aβ peptides is inhibition of the γ-secretase enzyme, which cleaves amyloid precursor protein to form Aβ peptides. We studied the in vivo effects of the potent, orally bioavailable and brain penetrant γ-secretase inhibitor (GSI), MRK-560, on both Aβx-40 and Aβx-42 in multiple compartments (plasma, the brain and cerebrospinal fluid) of rat. Although there were differences in the time course and magnitude of the changes, the results showed that MRK-560 caused marked inhibition of both Aβx-40 and Aβx-42 in all three compartments. We identified good correlations between plasma Aβx-40 versus brain Aβx-40 (r = 0.84), and plasma Aβx-40 versus CSF Aβx-40 (r = 0.85), indicating that these pools of Aβ are related dynamically. These results suggest that central Aβ changes that occur following acute dosing with MRK-560 can be predicted based on plasma Aβ changes and could thus serve as a useful biomarker to help accelerate decision-making during early clinical development.
authors.affiliation: 1Departments of Molecular Biomarkers.
authors.forename: Guoxin
authors.initials: G
authors.lastname: Wu
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Wu
authors.forename: Sang
authors.initials: S
authors.lastname: Na
authors.forename: James C
authors.initials: JC
authors.lastname: Hershey
mesh_terms: D000284:Administration, Oral; D016229:Amyloid beta-Peptides / Q000097:blood* / Q000134:cerebrospinal fluid*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013223:Statistics as Topic; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; C510791:MRK 560; D013449:Sulfonamides
keywords: Alzheimer's disease; amyloid beta; animal models; γ-secretase