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

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.

Keywords: Alzheimer’s disease; Biomarkers; Extracellular vesicles; Mesenchymal stem cells; Therapeutics.

Fig. 1.

Biomarker potential of L1CAM + extracellular vesicles (EVs) in Alzheimer’s disease (AD). Schematic representation of identified biomarker candidates (boxes) and their idealized levels (graphs) in control (ctrl), preclinical AD (pAD) and AD patients. (A-D) Idealized data based on longitudinal studies analyzing repeated samples of a single patient prior to (pAD) and after diagnosis (AD), compared to controls. The level of some biomarker candidates already plateaus at the pAD stage (A, C), allowing the identification of patients at an early disease stage before the occurrence of clinical symptoms (i.e., preclinical biomarkers). The levels of other biomarker candidates are intermediary changed at the pAD stage (B, D), allowing the differentiation between different stages of AD and follow-up of disease progression (i.e., prognostic biomarkers). (E-F) Idealized data based on studies comparing biomarker candidates between AD patients and controls, allowing the differentiation between AD patients and controls (i.e., diagnostic biomarkers). Abbreviations: AMPA4: GluA4-containing glutamate; Aβ: amyloid beta; GAP43: growth-associated protein 43; HSF1: heat-shock factor-1; HSP70: H-heat-shock protein 70; IRS-1: insulin receptor substrate-1; LAMP1: lysosome-associated membrane protein 1; LRP6: lipoprotein receptor-related protein 6; NLGN1: neuroligin 1; NPTX2: neuronal pentraxin 2; NRGN: neurogranin; NRXN2α: neurexin 2α; REST: repressor element 1-silencing transcription factor; sAPP: soluble amyloid precursor protein; SNAP-25: synaptosomal-associated-protein 25.

Fig. 2.

Biomarker potential of NCAM+, CSPG4/PDGFRα + and GLAST + extracellular vesicles (EVs) in Alzheimer’s disease (AD). Schematic representation of identified biomarker candidates (boxes) and their idealized levels (graphs) in control (ctrl), mild cognitive impairment (MCI) and AD patients in (A) presumably neuronal-derived, NCAM + EVs, (B) presumably endothelial-enriched, CSPG4 and PDGFRα + EVs and (C-F) presumably astrocyte-derived, GLAST + EVs Panel B-D show idealized data based on longitudinal studies analyzing repeated samples of a single patient prior to (pAD) and after diagnosis (AD), compared to controls. The level of some biomarker candidates already plateaus at the pAD stage (B), allowing the identification of patients at an early disease stage before the occurrence of clinical symptoms (i.e., preclinical biomarkers). The levels of other biomarker candidates are intermediary changed at the pAD (A,D) or MCI (A) stage, allowing the differentiation between different stages of AD and follow-up of disease progression (i.e., prognostic biomarkers). Abbreviations: Aβ: amyloid beta; BACE1: β-site APP cleaving enzyme-1; CSPG4: Chondroitin sulfate proteoglycan 4; DAF: Decay-accelerating factor; FGF: Fibroblast growth factor; GLAST: Glutamine aspartate transporter; HGF: Hepatocyte growth factor; IGF: Insulin-like growth factor; IL: interleukin; NCAM: Neural cell adhesion molecule; PDGFRα: anti-platelet growth factor receptor alpha; sAPPβ: soluble amyloid precursor protein beta; t-Tau: total Tau; TNF: tumor necrosis factor.