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

Abstract

The accumulation of amyloid ␤ (A␤) in Alzheimer's disease is caused by an imbalance of production and clearance, which leads to increased soluble A␤ species and extracellular plaque formation in the brain. Multiple A␤-lowering therapies are currently in development: an important goal is to characterize the molecular mechanisms of action and effects on physiological processing of A␤, as well as other amyloid precursor protein (APP) metabolites, in models which approximate human A␤ 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 ␥-secretase inhibitor (GSI). A major concern of inhibiting the enzymes which produce A␤ (␤-and ␥-secretase) is that precursors of A␤ may accumulate and cause a rapid increase in A␤ 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␤. In contrast to systemic A␤ metabolism, CNS A␤ 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␤, including C-terminal truncated forms of A␤: 1-14, 1-15 and 1-16; this demonstrates an alternative degradation pathway for CNS amyloid precursor protein during ␥-secretase inhibition.

Mechanistic Pharmacokinetic-Pharmacodynamic Modeling of BACE1 Inhibition in Monkeys: Development of a Predictive Model for Amyloid Precursor Protein Processing

“…) and half-life (8.3 hours) in monkeys (Cook et al, 2010). A similar elimination rate constant was also observed in humans (Bateman et al, 2006).…”

Site-specific characterization of threonine, serine, and tyrosine glycosylations of amyloid precursor protein/amyloid β-peptides in human cerebrospinal fluid

“…Altogether 33 different Aβ peptides were identified (SI Appendix, Table S1) some of which, e.g., Aβ1-15, previously identified as a positive biomarker of γ-secretase inhibition (22,23), constituted less than 1% of the total ion current chromatogram. No sign of any glycosylated derivatives of Aβ1-40 (SI Appendix, Fig.…”

Differential Effects between γ-Secretase Inhibitors and Modulators on Cognitive Function in Amyloid Precursor Protein-Transgenic and Nontransgenic Mice

“…This attenuation may be due to a shift from ␤-cleavage to ␣-cleavage of APP, as the concurrent increase in sAPP␣ and decrease in sAPP␤ in the media were seen by ELISA (data not shown). Alternatively, enhanced cleavage of ␤-CTF by ␣-secretase could also be a possible explanation (Beher et al, 2002;Cook et al, 2010;Portelius et al, 2011).…”