Acute gamma-Secretase Inhibition of Nonhuman Primate CNS Shifts Amyloid Precursor Protein (APP) Metabolism from Amyloid-beta Production to Alternative APP Fragments without Amyloid-beta Rebound

作者：Cook Jacquelynn J; Wildsmith Kristin R; Gilberto David B; Holahan Marie A; Kinney Gene G; Mathers Parker D; Michener Maria S; Price Eric A; Shearman Mark S; Simon Adam J; Wang Jennifer X; Wu Guoxin; Yarasheski Kevin E; Bateman Randall J^*

来源：Journal of Neuroscience, 2010, 30(19): 6743-6750.

DOI：10.1523/JNEUROSCI.1381-10.2010

The accumulation of amyloid beta (A beta) in Alzheimer's disease is caused by an imbalance of production and clearance, which leads to increased soluble A beta species and extracellular plaque formation in the brain. Multiple A beta-lowering therapies are currently in development: an important goal is to characterize the molecular mechanisms of action and effects on physiological processing of A beta, as well as other amyloid precursor protein (APP) metabolites, in models which approximate human A beta physiology. To this end, we report the translation of the human in vivo stable-isotope-labeling kinetics (SILK) method to a rhesus monkey cisterna magna ported (CMP) nonhuman primate model, and use the model to test the mechanisms of action of a gamma-secretase inhibitor (GSI). A major concern of inhibiting the enzymes which produce A beta (beta- and gamma-secretase) is that precursors of A beta may accumulate and cause a rapid increase in A beta production when enzyme inhibition discontinues. In this study, the GSI MK-0752 was administered to conscious CMP rhesus monkeys in conjunction with in vivo stable-isotope-labeling, and dose-dependently reduced newly generated CNS A beta. In contrast to systemic A beta metabolism, CNS A beta production was not increased after the GSI was cleared. These results indicate that most of the CNS APP was metabolized to products other than A beta, including C-terminal truncated forms of A beta : 1-14, 1-15 and 1-16; this demonstrates an alternative degradation pathway for CNS amyloid precursor protein during gamma-secretase inhibition.

• 出版日期2010-5-12