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Extracellular Vesicles Slow Down Aβ(1−42) Aggregation by Interfering with the Amyloid Fibril Elongation Step

Halipi, Vesa ; Sasanian, Nima ; Feng, Julia ; Hu, Jing LU ; Lubart, Quentin ; Bernson, David ; van Leeuwen, Daniel ; Ahmadpour, Doryaneh ; Sparr, Emma LU and Esbjörner, Elin K. (2024) In ACS Chemical Neuroscience 15(5). p.944-954
Abstract

Formation of amyloid-β (Aβ) fibrils is a central pathogenic feature of Alzheimer's disease. Cell-secreted extracellular vesicles (EVs) have been suggested as disease modulators, although their exact roles and relations to Aβ pathology remain unclear. We combined kinetics assays and biophysical analyses to explore how small (<220 nm) EVs from neuronal and non-neuronal human cell lines affected the aggregation of the disease-associated Aβ variant Aβ(1−42) into amyloid fibrils. Using thioflavin-T monitored kinetics and seeding assays, we found that EVs reduced Aβ(1−42) aggregation by inhibiting fibril elongation. Morphological analyses revealed this to result in the formation of short fibril fragments with increased thicknesses and less... (More)

Formation of amyloid-β (Aβ) fibrils is a central pathogenic feature of Alzheimer's disease. Cell-secreted extracellular vesicles (EVs) have been suggested as disease modulators, although their exact roles and relations to Aβ pathology remain unclear. We combined kinetics assays and biophysical analyses to explore how small (<220 nm) EVs from neuronal and non-neuronal human cell lines affected the aggregation of the disease-associated Aβ variant Aβ(1−42) into amyloid fibrils. Using thioflavin-T monitored kinetics and seeding assays, we found that EVs reduced Aβ(1−42) aggregation by inhibiting fibril elongation. Morphological analyses revealed this to result in the formation of short fibril fragments with increased thicknesses and less apparent twists. We suggest that EVs may have protective roles by reducing Aβ(1−42) amyloid loads, but also note that the formation of small amyloid fragments could be problematic from a neurotoxicity perspective. EVs may therefore have double-edged roles in the regulation of Aβ pathology in Alzheimer's disease.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer's disease, amyloid kinetics, amyloid-β, EVs, extracellular vesicles, protein aggregation
in
ACS Chemical Neuroscience
volume
15
issue
5
pages
11 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • pmid:38408014
  • scopus:85186102141
ISSN
1948-7193
DOI
10.1021/acschemneuro.3c00655
language
English
LU publication?
yes
id
8fab519e-a78f-4d18-8f75-0fac360a177d
date added to LUP
2024-03-19 15:43:03
date last changed
2025-05-01 02:12:44
@article{8fab519e-a78f-4d18-8f75-0fac360a177d,
  abstract     = {{<p>Formation of amyloid-β (Aβ) fibrils is a central pathogenic feature of Alzheimer's disease. Cell-secreted extracellular vesicles (EVs) have been suggested as disease modulators, although their exact roles and relations to Aβ pathology remain unclear. We combined kinetics assays and biophysical analyses to explore how small (&lt;220 nm) EVs from neuronal and non-neuronal human cell lines affected the aggregation of the disease-associated Aβ variant Aβ(1−42) into amyloid fibrils. Using thioflavin-T monitored kinetics and seeding assays, we found that EVs reduced Aβ(1−42) aggregation by inhibiting fibril elongation. Morphological analyses revealed this to result in the formation of short fibril fragments with increased thicknesses and less apparent twists. We suggest that EVs may have protective roles by reducing Aβ(1−42) amyloid loads, but also note that the formation of small amyloid fragments could be problematic from a neurotoxicity perspective. EVs may therefore have double-edged roles in the regulation of Aβ pathology in Alzheimer's disease.</p>}},
  author       = {{Halipi, Vesa and Sasanian, Nima and Feng, Julia and Hu, Jing and Lubart, Quentin and Bernson, David and van Leeuwen, Daniel and Ahmadpour, Doryaneh and Sparr, Emma and Esbjörner, Elin K.}},
  issn         = {{1948-7193}},
  keywords     = {{Alzheimer's disease; amyloid kinetics; amyloid-β; EVs; extracellular vesicles; protein aggregation}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{944--954}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{ACS Chemical Neuroscience}},
  title        = {{Extracellular Vesicles Slow Down Aβ(1−42) Aggregation by Interfering with the Amyloid Fibril Elongation Step}},
  url          = {{http://dx.doi.org/10.1021/acschemneuro.3c00655}},
  doi          = {{10.1021/acschemneuro.3c00655}},
  volume       = {{15}},
  year         = {{2024}},
}