Quantitative Assessment Of A Beta Peptide In Brain, Cerebrospinal Fluid And Plasma Following Oral Administration Of Gamma-Secretase Inhibitor Mrk-560 In Rats

The beta-amyloid peptides (A beta) 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 A beta peptides is inhibition of the. -secretase enzyme, which cleaves amyloid precursor protein to form A beta peptides. We studied the in vivo effects of the potent, orally bioavailable and brain penetrant gamma-secretase inhibitor (GSI), MRK-560, on both A beta x-40 and A beta x-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 A beta x-40 and A beta x-42 in all three compartments. We identified good correlations between plasma A beta x-40 versus brain A beta x-40 (r = 0.84), and plasma A beta x-40 versus CSF A beta x-40 (r = 0.85), indicating that these pools of A beta are related dynamically. These results suggest that central A beta changes that occur following acute dosing with MRK-560 can be predicted based on plasma A beta changes and could thus serve as a useful biomarker to help accelerate decision-making during early clinical development.