Abstract

AbstractBackgroundWe have previously identified APP669‐711 (a.k.a. Aβ(‐3)‐40) in human plasma using immunoprecipitation combined with matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry (IP‐MALDI‐MS) (Kaneko et al., Proc Jpn Acad Ser B Phys Biol Sci. 2014). Our assay has revealed that the composite biomarker, which is a combination of APP669‐711/Aβ1‐42 ratio and Aβ1‐40/ Aβ1‐42 ratio in human plasma, correlates with amyloid PET status (Nakamura et al., Nature 2018). However, the significance of these peptide ratios in an APP/PS1 mouse model of Alzheimer's disease has been unclear. In this study, we investigated the levels of Aβ‐related peptides including APP669‐711 in plasma samples from the model mouse.MethodWe prepared plasma samples from young (2 months of age) and old (23–25 months of age) APP/PS1 mice expressing both APP bearing the Swedish mutation and PSEN1 harboring ΔE9 mutation, and cultured supernatants of HEK293 cells. Mouse plasma samples and cultured supernatants were measured by IP‐MALDI‐MS.ResultHuman APP669‐711 was detected in cultured supernatant of HEK293 cells overexpressing human wild‐type APP but not human APP with the Swedish mutation. This result indicated that two amino acid substitutions (i.e., Swedish mutation) near the APP669 site inhibited the APP669 cleavage and the production of APP669‐711 from the transgene of APP/PS1 mice. Then we focused on mouse endogenous murine Aβ‐related peptides in the evaluation of plasma biomarker for the amyloid deposition in the brains of APP/PS1 mice. The analysis of APP/PS1 mouse plasma showed that murine APP669‐711/Aβ1‐42 and APP669‐711/Aβ1‐40 ratios were increased in old mice with plaques compared to young mice without them. However, the murine Aβ1‐40/Aβ1‐42 ratio was not changed between old and young mice.ConclusionThese results suggested that the APP669‐711/Aβ1‐42 ratio is a common biomarker for the amyloid plaque pathology in humans and APP/PS1 mice. Also, we revealed the possibility that the APP669‐711/Aβ1‐40 ratio is a biomarker specific for the brain Aβ deposition in APP/PS1 mice. These biomarkers can be useful tools to study lifestyle intervention and drug development for the prevention of amyloid deposition using the model mouse.

Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call