Subtyping of circulating exosome-bound amyloid \u03b2 reflects brain plaque deposition

Carine Z J Lim,Yan Zhang,Haitao Zhao,Yu Chen,Christopher L H Chen,Huilin Shao,Mary C Stephenson,Tze Ping Loh,Jaehoon Chung,Anthonin Reilhac,Nicholas R Y Ho,Yuan Chen

doi:10.1038/s41467-019-09030-2

Abstract

Despite intense interests in developing blood measurements of Alzheimer’s disease (AD), the progress has been confounded by limited sensitivity and poor correlation to brain pathology. Here, we present a dedicated analytical platform for measuring different populations of circulating amyloid β (Aβ) proteins – exosome-bound vs. unbound – directly from blood. The technology, termed amplified plasmonic exosome (APEX), leverages in situ enzymatic conversion of localized optical deposits and double-layered plasmonic nanostructures to enable sensitive, multiplexed population analysis. It demonstrates superior sensitivity (~200 exosomes), and enables diverse target co-localization in exosomes. Employing the platform, we find that prefibrillar Aβ aggregates preferentially bind with exosomes. We thus define a population of Aβ as exosome-bound (Aβ42+ CD63+) and measure its abundance directly from AD and control blood samples. As compared to the unbound or total circulating Aβ, the exosome-bound Aβ measurement could better reflect PET imaging of brain amyloid plaques and differentiate various clinical groups.

Highlights

Despite intense interests in developing blood measurements of Alzheimer’s disease (AD), the progress has been confounded by limited sensitivity and poor correlation to brain pathology
In light of the enhanced binding between exosomes and prefibrillar amyloid β (Aβ) aggregates, the building blocks of amyloid plaques, we hypothesized that exosome-bound Aβ could serve as a more reflective circulating biomarker of brain plaque load
Despite intense interests in developing blood-based AD measurements, their progress has been confounded by limited sensitivity and poor correlation to brain pathology

Summary

Introduction

Despite intense interests in developing blood measurements of Alzheimer’s disease (AD), the progress has been confounded by limited sensitivity and poor correlation to brain pathology. We present a dedicated analytical platform for measuring different populations of circulating amyloid β (Aβ) proteins – exosome-bound vs unbound – directly from blood. The technology, termed amplified plasmonic exosome (APEX), leverages in situ enzymatic conversion of localized optical deposits and double-layered plasmonic nanostructures to enable sensitive, multiplexed population analysis. As compared to the unbound or total circulating Aβ, the exosome-bound Aβ measurement could better reflect PET imaging of brain amyloid plaques and differentiate various clinical groups. The most common form of severe dementia, AD is characterized by a progressive loss of memory and cognitive functions Long before these full-blown clinical symptoms appear, AD molecular hallmarks, notably extracellular amyloid β (Aβ) plaques, may manifest and advance[1]. One possible reason for this could arise from the different measurement methodologies

Methods

Results

Conclusion