Biomarker and therapeutic potential of peripheral extracellular vesicles in Alzheimer’s disease

https://doi.org/10.1016/j.addr.2022.114486Get rights and content

Abstract

Extracellular vesicles (EVs) are cell-derived nanoparticles with an important role in intercellular communication, even across brain barriers. The bidirectional brain-barrier crossing capacity of EVs is supported by research identifying neuronal markers in peripheral EVs, as well as the brain delivery of peripherally administered EVs. In addition, EVs are reflective of their cellular origin, underlining their biomarker and therapeutic potential when released by diseased and regenerative cells, respectively. Both characteristics are of interest in Alzheimer’s disease (AD) where the current biomarker profile is solely based on brain-centered readouts and effective therapeutic options are lacking. In this review, we elaborate on the role of peripheral EVs in AD. We focus on bulk EVs and specific EV subpopulations including bacterial EVs (bEVs) and neuronal-derived EVs (nEVs), which have mainly been studied from a biomarker perspective. Furthermore, we highlight the therapeutic potential of peripherally administered EVs whereby research has centered around stem cell derived EVs.

Introduction

Intercellular communication is of vital importance for multicellular organisms. Communication can occur via different mechanisms including direct cell–cell contact, secretion of signalling molecules (e.g., hormones, neurotransmitters, cytokines), tunnelling nanotubes, non-membranous extracellular particles (exomeres) as well as extracellular vesicles (EVs). EVs comprise a heterogenous population of nanosized particles enclosed by a lipid membrane that seem to be secreted by all cell-types[1]. Based on their mode of biogenesis, EVs can be divided in two main categories: ectosomes (including microvesicles) and exosomes whereby both categories contain multiple EV subtypes. Distinguishing between the EV subtypes based on their size is challenging given their overlapping size range and the heterogeneity of this size range that is reported in literature. Furthermore, there is currently no consensus on the characterization of EV subtypes based on their protein composition[2]. Therefore, as supported by the minimal information for studies of EVs (MISEV) guidelines[3], we will consistently use the generic term “EV” throughout this review. The cargo (e.g., proteins, lipids, and genetic material) of EVs is encapsulated in a membrane bilayer and thereby is shielded from dilution or degradation in the extracellular environment, allowing protected transport to both adjacent and distant target cells, even across brain barriers. This concept of brain-to-periphery and periphery-to-brain communication mediated by EVs underlies their potential as a source of biomarkers and brain (drug) delivery vehicles, respectively. In this review, we elaborate on the role of peripheral EVs in AD, which has mainly been studied in a biomarker context. Furthermore, we compile literature describing the therapeutic capacity of EVs in AD and touch upon some challenges inherently linked to this approach.

Section snippets

Peripheral EVs in AD

EVs are present in a variety of peripheral biofluids, including blood, urine and saliva. The accessibility of these fluids in combination with the fact that EV composition is reflective of their cellular origin sparked enthusiasm for their capacity as a source of biomarkers. Biomarkers are of particular interest for neurodegenerative diseases including AD, for which clinical diagnosis is only possible when considerable and irreversible neuronal damage has already occurred. Current guidelines

Evs as a treatment for AD

Based on their presumed CNS barrier crossing capacity and inherent characteristics including biological cargo protection and low immunogenicity, EVs have been suggested as promising brain (drug) delivery vehicles[79]. In this review, we will discuss the available data on EVs as potential therapeutics for AD.

Practical considerations towards EVs as biomarkers and therapeutics

Despite promising results in various model systems, it remains important to reflect on potential limitations of EVs as a treatment for AD. Some of these apply to the interpretation of the obtained results (e.g., as discussed for the brain delivery of therapeutic EVs), others to the clinical translatability of EV treatments applied to model systems. Similar practical hurdles need to be taken into account when exploring EVs as biomarker sources. Here, we briefly discuss several considerations,

Conclusions

To facilitate the development of effective treatments for AD, it is imperative to detect the disease at its preclinical and, potentially, modifiable stage, before brain damage is irreversible. This underlines the pressing need for developing biomarkers for preclinical and early clinical diagnosis when patients might benefit the most from disease-modifying drugs once these become available. Additionally, biomarkers are also instrumental for monitoring disease progression and evaluating the

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work was supported by the Special Research Fund (BOF) of Ghent University, the Research Foundation Flanders (FWO Vlaanderen; V417921N), the Foundation for Alzheimer’s Research (SAO-FRA), VIB, the Baillet Latour Fund, and the Intramular Research Program of the National Institute on Aging, NIH. The Figures were created using BioRender.com.

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    Dimitrios Kapogiannis and Roosmarijn E. Vandenbroucke share senior authorship.

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