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Cited by 29Extracellular vesicles in diseaseAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

Differential Profile of Systemic Extracellular Vesicles From Sporadic and Familial Alzheimer’s Disease Leads to Neuroglial and Endothelial Cell Degeneration

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Villar-Vesga, Juan, Henao-Restrepo, Julián, Voshart, Daniëlle C., Aguillon, David, Villegas, Andrés, Castaño, Diana, Arias-Londoño, Julián D., Zuhorn, Inge S. +4 more·2020·Frontiers in Aging Neuroscience
DOI 10.3389/fnagi.2020.587989PMC PMC7705379
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Abstract

Evidence suggests that extracellular vesicles (EVs) act as mediators and biomarkers of neurodegenerative diseases. Two distinct forms of Alzheimer disease (AD) are known: a late-onset sporadic form (SAD) and an early-onset familial form (FAD). Recently, neurovascular dysfunction and altered systemic immunological components have been linked to AD neurodegeneration. Therefore, we characterized systemic-EVs from postmortem SAD and FAD patients and evaluated their effects on neuroglial and endothelial cells. We found increase CLN-5 spots with vesicular morphology in the abluminal portion of vessels from SAD patients. Both forms of AD were associated with larger and more numerous systemic EVs. Specifically, SAD patients showed an increase in endothelial- and leukocyte-derived EVs containing mitochondria; in contrast, FAD patients showed an increase in platelet-derived EVs. We detected a differential protein composition for SAD- and FAD-EVs associated with the coagulation cascade, inflammation, and lipid-carbohydrate metabolism. Using mono- and cocultures (endothelium-astrocytes-neurons) and human cortical organoids, we showed that AD-EVs induced cytotoxicity. Both forms of AD featured decreased neuronal branches area and astrocytic hyperreactivity, but SAD-EVs led to greater endothelial detrimental effects than FAD-EVs. In addition, FAD- and SAD-EVs affected calcium dynamics in a cortical organoid model. Our findings indicate that the phenotype of systemic AD-EVs is differentially defined by the etiopathology of the disease (SAD or FAD), which results in a differential alteration of the NVU cells implied in neurodegeneration.

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  • Systemic extracellular vesicles interact directly with endothelial cells and can cross the blood-brain barrier to reach the brain parenchyma.

    “We demonstrated that systemic EVs interact directly with endothelial cells and can cross the blood–brain barrier (BBB) to reach the brain parenchyma. 24”

    From Plasma extracellular vesicles from <i>APOE3</i> Christchurch carriers display a protective phenotype in early stages of autosomal dominant Alzheimer's disease (2026) · cites this paper as [24]

    The Results section reports that systemic EVs crossed a human brain microvasculature cell layer and affected endothelial cells; the Discussion says AD-EVs interacted with neurovascular-unit cells. But the BBB-crossing test was an in vitro model, so the paper does not demonstrate that the EVs reached brain parenchyma in vivo. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Blood serum‐derived extracellular vesicles from FAD are associated with inflammatory‐related factors to a greater extent than those from SAD.

    “blood serum‐derived extracellular vesicles from FAD are associated with inflammatory‐related factors to a greater extent than those from SAD [73].”

    From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [73]

    The Results section (page unavailable) reports that immunoglobulins were higher in FAD-derived EVs than in SAD-derived EVs and suggests that the differing protein profiles may relate to inflammation. It does not establish that inflammation-related factors overall are more associated with FAD-derived EVs; some other proteins also differ in the opposite direction. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Previous studies of our group have identified molecular differences between SAD and FAD in addition to divergences in clinical manifestations.

    “Previous studies of our group have identified molecular differences between SAD and FAD [55, 56, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79] in addition to divergences in the clinical manifestations [55, 56].”

    From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [73]

  • Potentially claudin-5-positive extracellular vesicles increase near the vessels of the frontal cortex in a manner that differentiates sporadic Alzheimer's disease (SAD) from familial Alzheimer's disease (FAD).

    “we had previously shown that potentially claudin‐5‐positive extracellular vesicles increase near the vessels of the frontal cortex in a manner that differentiates SAD from FAD [73]”

    From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [73]

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Cited by

Sorted by citations

Authors
Villar-Vesga, J., Henao-Restrepo, J., Voshart, D. C., Aguillon, D., Villegas, A., Castaño, D., Arias-Londoño, J. D., Zuhorn, I. S., Ribovski, L., Barazzuol, L., Cardona-Gómez, G. P., & Posada-Duque, R.
Affiliations
  • Universidad de Antioquia (CO)
  • University Medical Center Groningen (NL)
ORCID
Venue
Frontiers in Aging Neuroscience
Publisher
Frontiers Media SA
Published
2020-11-11
Volume
12
Pages
587989-587989
ISSN
1663-4365 (ISSN-L)
DOI
10.3389/fnagi.2020.587989
PMC
PMC7705379
OpenAlex
W3098588635
Cited by
29
References
12
Citations by year
2026: 5 · 2025: 3 · 2024: 7 · 2023: 5 · 2022: 4 · 2021: 5
FWCI
1.12
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Aging Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Institutional Repository University of Antioquia (University of Antioquia) (publishedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
  • Greater South Information System
Funders
Departamento Administrativo de Ciencia, Tecnología e Innovación
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, sporadic Alzheimer's disease, familial Alzheimer's disease, extracellular vesicles, neurovascular unit, endothelial cells, astrocytes, platelet-derived extracellular vesicles, mitochondrial vesicles, coagulation cascade, neuroinflammation, lipid metabolism, neuronal calcium dynamics, cortical organoids, neurodegeneration, biomarkers

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