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A Kinetic Map of the Influence of Biomimetic Lipid Model Membranes on Aβ42 Aggregation

Baumann, Kevin N. ; Šneiderienė, Greta ; Sanguanini, Michele ; Schneider, Matthias ; Rimon, Oded ; González Díaz, Alicia ; Greer, Heather ; Thacker, Dev LU ; Linse, Sara LU and Knowles, Tuomas P.J. , et al. (2023) In ACS Chemical Neuroscience 14(2). p.323-329
Abstract

The aggregation of the amyloid β (Aβ) peptide is one of the molecular hallmarks of Alzheimer’s disease (AD). Although Aβ deposits have mostly been observed extracellularly, various studies have also reported the presence of intracellular Aβ assemblies. Because these intracellular Aβ aggregates might play a role in the onset and progression of AD, it is important to investigate their possible origins at different locations of the cell along the secretory pathway of the amyloid precursor protein, from which Aβ is derived by proteolytic cleavage. Senile plaques found in AD are largely composed of the 42-residue form of Aβ (Aβ42). Intracellularly, Aβ42 is produced in the endoplasmatic reticulum (ER) and Golgi... (More)

The aggregation of the amyloid β (Aβ) peptide is one of the molecular hallmarks of Alzheimer’s disease (AD). Although Aβ deposits have mostly been observed extracellularly, various studies have also reported the presence of intracellular Aβ assemblies. Because these intracellular Aβ aggregates might play a role in the onset and progression of AD, it is important to investigate their possible origins at different locations of the cell along the secretory pathway of the amyloid precursor protein, from which Aβ is derived by proteolytic cleavage. Senile plaques found in AD are largely composed of the 42-residue form of Aβ (Aβ42). Intracellularly, Aβ42 is produced in the endoplasmatic reticulum (ER) and Golgi apparatus. Since lipid bilayers have been shown to promote the aggregation of Aβ, in this study, we measure the effects of the lipid membrane composition on the in vitro aggregation kinetics of Aβ42. By using large unilamellar vesicles to model cellular membranes at different locations, including the inner and outer leaflets of the plasma membrane, late endosomes, the ER, and the Golgi apparatus, we show that Aβ42 aggregation is inhibited by the ER and Golgi model membranes. These results provide a preliminary map of the possible effects of the membrane composition in different cellular locations on Aβ aggregation and suggest the presence of an evolutionary optimization of the lipid composition to prevent the intracellular aggregation of Aβ.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
aggregation kinetics, Alzheimer’s disease, amyloid β, cryo-electron microscopy, lipid membranes, protein aggregation
in
ACS Chemical Neuroscience
volume
14
issue
2
pages
7 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • scopus:85145302143
  • pmid:36574473
ISSN
1948-7193
DOI
10.1021/acschemneuro.2c00765
language
English
LU publication?
yes
id
85a55645-429e-41b5-a239-e4d8e00508bd
date added to LUP
2023-02-09 13:47:43
date last changed
2024-06-25 15:13:20
@article{85a55645-429e-41b5-a239-e4d8e00508bd,
  abstract     = {{<p>The aggregation of the amyloid β (Aβ) peptide is one of the molecular hallmarks of Alzheimer’s disease (AD). Although Aβ deposits have mostly been observed extracellularly, various studies have also reported the presence of intracellular Aβ assemblies. Because these intracellular Aβ aggregates might play a role in the onset and progression of AD, it is important to investigate their possible origins at different locations of the cell along the secretory pathway of the amyloid precursor protein, from which Aβ is derived by proteolytic cleavage. Senile plaques found in AD are largely composed of the 42-residue form of Aβ (Aβ<sub>42</sub>). Intracellularly, Aβ<sub>42</sub> is produced in the endoplasmatic reticulum (ER) and Golgi apparatus. Since lipid bilayers have been shown to promote the aggregation of Aβ, in this study, we measure the effects of the lipid membrane composition on the in vitro aggregation kinetics of Aβ<sub>42</sub>. By using large unilamellar vesicles to model cellular membranes at different locations, including the inner and outer leaflets of the plasma membrane, late endosomes, the ER, and the Golgi apparatus, we show that Aβ<sub>42</sub> aggregation is inhibited by the ER and Golgi model membranes. These results provide a preliminary map of the possible effects of the membrane composition in different cellular locations on Aβ aggregation and suggest the presence of an evolutionary optimization of the lipid composition to prevent the intracellular aggregation of Aβ.</p>}},
  author       = {{Baumann, Kevin N. and Šneiderienė, Greta and Sanguanini, Michele and Schneider, Matthias and Rimon, Oded and González Díaz, Alicia and Greer, Heather and Thacker, Dev and Linse, Sara and Knowles, Tuomas P.J. and Vendruscolo, Michele}},
  issn         = {{1948-7193}},
  keywords     = {{aggregation kinetics; Alzheimer’s disease; amyloid β; cryo-electron microscopy; lipid membranes; protein aggregation}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{2}},
  pages        = {{323--329}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{ACS Chemical Neuroscience}},
  title        = {{A Kinetic Map of the Influence of Biomimetic Lipid Model Membranes on Aβ<sub>42</sub> Aggregation}},
  url          = {{http://dx.doi.org/10.1021/acschemneuro.2c00765}},
  doi          = {{10.1021/acschemneuro.2c00765}},
  volume       = {{14}},
  year         = {{2023}},
}