Abstract
Blood-circulating biomarkers have the potential to detect Alzheimer’s disease (AD) pathology before clinical symptoms emerge and to improve the outcomes of clinical trials for disease-modifying therapies. Despite recent advances in understanding concomitant systemic abnormalities, there are currently no validated or clinically used blood-based biomarkers for AD. The extremely low concentration of neurodegeneration-associated proteins in blood necessitates the development of analytical platforms to address the “signal-to-noise” issue and to allow an in-depth analysis of the plasma proteome. Here, we aimed to discover and longitudinally track alterations of the blood proteome in a transgenic mouse model of AD, using a nanoparticle-based proteomics enrichment approach. We employed blood-circulating, lipid-based nanoparticles to extract, analyze and monitor AD-specific protein signatures and to systemically uncover molecular pathways associated with AD progression. Our data revealed the existence of multiple proteomic signals in blood, indicative of the asymptomatic stages of AD. Comprehensive analysis of the nanoparticle-recovered blood proteome by label-free liquid chromatography–tandem mass spectrometry resulted in the discovery of AD-monitoring signatures that could discriminate the asymptomatic phase from amyloidopathy and cognitive deterioration. While the majority of differentially abundant plasma proteins were found to be upregulated at the initial asymptomatic stages, the abundance of these molecules was significantly reduced as a result of amyloidosis, suggesting a disease-stage-dependent fluctuation of the AD-specific blood proteome. The potential use of the proposed nano-omics approach to uncover information in the blood that is directly associated with brain neurodegeneration was further exemplified by the recovery of focal adhesion cascade proteins. We herein propose the integration of nanotechnology with already existing proteomic analytical tools in order to enrich the identification of blood-circulating signals of neurodegeneration, reinvigorating the potential clinical utility of the blood proteome at predicting the onset and kinetics of the AD progression trajectory.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder that results in a progressive and irreversible loss of memory and cognition.[1]
The double transgenic mouse model of AD, APPswe/PS 1dE9,24 was employed, and plaque deposition and memory deficits were assessed in APPswe PSEN1ΔE9 (APP/PS1) and WT control mice at 2, 6, and 12 months of age utilizing the amyloid-β (6e10 antibody) staining and the Morris Water Maze (MWM) test, respectively (Figure 1a−d)
To assess the enrichment of ADmonitoring proteomic signatures in blood, which could distinguish the asymptomatic phase from mild amyloidopathy and cognitive deterioration, we further investigated the temporal evolution of corona formation in APP/PS1 mice at 2, 6, and 12 months of age, by statistically comparing the respective corona profiles
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder that results in a progressive and irreversible loss of memory and cognition.[1]. Currently there is no effective disease-modifying therapy for AD and existing pharmacological treatments are solely used to ameliorate symptoms.[2]. The implementation of effective treatments that can directly target the underlying mechanism of AD has largely failed so far, mainly due to the lack of early diagnostic tools.[2] By the time symptoms emerge, the pathology is already wellestablished in the brain with the accumulation of amyloid-β plaques preceding cognitive symptoms by 10−15 years.[1] Stratification biomarkers that can detect the asymptomatic onset of AD could dramatically improve the outcomes of clinical trials for disease-modifying therapies, which are Received: January 24, 2021 Accepted: March 10, 2021 Published: March 17, 2021
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