Quantitative assessment of Aβ peptide in brain, cerebrospinal fluid and plasma following oral administration of γ-secretase inhibitor MRK-560 in rats

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.