The metabolism of human soluble amyloid precursor protein isoforms is quantifiable by a stable isotope labeling-tandem mass spectrometry method.

Evidence suggests that ß-secretase (BACE1), which cleaves Amyloid Precursor Protein (APP) to form sAPPß and amyloid-ß, is elevated in Alzheimer's disease (AD) brains and biofluids and, thus, BACE1 is a therapeutic target for this devastating disease. The direct product of BACE1 cleavage of APP, sAPPß, serves as a surrogate marker of BACE1 activity in the central nervous system. This biomarker could be utilized to better understand normal APP processing, aberrant processing in the disease setting, and modulations to processing during therapeutic intervention. In this paper, we present a method for measuring the metabolism of sAPPß and another APP proteolytic product, sAPPα, in vivo in humans using stable isotope labeling kinetics, paired with immunoprecipitation and liquid chromatography/tandem mass spectrometry. The method presented herein is robust, reproducible, and precise, and allows for the study of these analytes by taking into account their full dynamic potential as opposed to the traditional methods of absolute concentration quantitation that only provide a static view of a dynamic system. A study of in vivo cerebrospinal fluid sAPPß and sAPPα kinetics using these methods could reveal novel insights into pathophysiological mechanisms of AD, such as increased BACE1 processing of APP.

A promising new γ-secretase modulator for Alzheimer's disease.

Effective and safe treatments for Alzheimer's disease (AD) have been an elusive target for scientists who have been working tirelessly to gain control over a disease that is affecting millions of people, with continually rising case numbers as the population ages. However, in this issue of JEM, Rynearson et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20202560) present a beacon of hope for this field with a preclinical evaluation of a potent and robust γ-secretase modulator (GSM).