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Retardation of Aβ42 fibril formation by apolipoprotein A-I and recombinant HDL particles

Frankel, Rebecca LU ; Sparr, Emma LU and Linse, Sara LU (2023) In Journal of Biological Chemistry 299(11).
Abstract

The double nucleation mechanism of amyloid β (Aβ) peptide aggregation is retained from buffer to cerebrospinal fluid (CSF) but with reduced rate of all microscopic processes. Here, we used a bottom-up approach to identify retarding factors in CSF. We investigated the Aβ42 fibril formation as a function of time in the absence and presence of apolipoprotein A-I (ApoA-I), recombinant high-density lipoprotein (rHDL) particles, or lipid vesicles. A retardation was observed in the presence of ApoA-I or rHDL particles, most pronounced with ApoA-I, but not with lipid vesicles. Global kinetic analysis implies that rHDL interferes with secondary nucleation. The effect of ApoA-I could best be described as an interference with secondary and to a... (More)

The double nucleation mechanism of amyloid β (Aβ) peptide aggregation is retained from buffer to cerebrospinal fluid (CSF) but with reduced rate of all microscopic processes. Here, we used a bottom-up approach to identify retarding factors in CSF. We investigated the Aβ42 fibril formation as a function of time in the absence and presence of apolipoprotein A-I (ApoA-I), recombinant high-density lipoprotein (rHDL) particles, or lipid vesicles. A retardation was observed in the presence of ApoA-I or rHDL particles, most pronounced with ApoA-I, but not with lipid vesicles. Global kinetic analysis implies that rHDL interferes with secondary nucleation. The effect of ApoA-I could best be described as an interference with secondary and to a smaller extent primary nucleation. Using surface plasmon resonance and microfluidics diffusional sizing analyses, we find that both rHDL and ApoA-I interact with Aβ42 fibrils but not Aβ42 monomer, thus the effect on kinetics seems to involve interference with the catalytic surface for secondary nucleation. The Aβ42 fibrils were imaged using cryogenic-electron microscopy and found to be longer when formed in the presence of ApoA-I or rHDL, compared to formation in buffer. A retarding effect, as observed in CSF, could be replicated using a simpler system, from key components present in CSF but purified from a CSF-free host. However, the effect of CSF is stronger implying the presence of additional retarding factors.

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author
; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
inhibition, neurodegeneration, plaque, suppression
in
Journal of Biological Chemistry
volume
299
issue
11
article number
105273
publisher
American Society for Biochemistry and Molecular Biology
external identifiers
  • pmid:37739034
  • scopus:85174446137
ISSN
0021-9258
DOI
10.1016/j.jbc.2023.105273
language
English
LU publication?
yes
id
49fc65e5-e922-48d0-94b5-c01e221784cc
date added to LUP
2023-12-07 14:53:11
date last changed
2024-02-20 09:59:03
@article{49fc65e5-e922-48d0-94b5-c01e221784cc,
  abstract     = {{<p>The double nucleation mechanism of amyloid β (Aβ) peptide aggregation is retained from buffer to cerebrospinal fluid (CSF) but with reduced rate of all microscopic processes. Here, we used a bottom-up approach to identify retarding factors in CSF. We investigated the Aβ42 fibril formation as a function of time in the absence and presence of apolipoprotein A-I (ApoA-I), recombinant high-density lipoprotein (rHDL) particles, or lipid vesicles. A retardation was observed in the presence of ApoA-I or rHDL particles, most pronounced with ApoA-I, but not with lipid vesicles. Global kinetic analysis implies that rHDL interferes with secondary nucleation. The effect of ApoA-I could best be described as an interference with secondary and to a smaller extent primary nucleation. Using surface plasmon resonance and microfluidics diffusional sizing analyses, we find that both rHDL and ApoA-I interact with Aβ42 fibrils but not Aβ42 monomer, thus the effect on kinetics seems to involve interference with the catalytic surface for secondary nucleation. The Aβ42 fibrils were imaged using cryogenic-electron microscopy and found to be longer when formed in the presence of ApoA-I or rHDL, compared to formation in buffer. A retarding effect, as observed in CSF, could be replicated using a simpler system, from key components present in CSF but purified from a CSF-free host. However, the effect of CSF is stronger implying the presence of additional retarding factors.</p>}},
  author       = {{Frankel, Rebecca and Sparr, Emma and Linse, Sara}},
  issn         = {{0021-9258}},
  keywords     = {{inhibition; neurodegeneration; plaque; suppression}},
  language     = {{eng}},
  number       = {{11}},
  publisher    = {{American Society for Biochemistry and Molecular Biology}},
  series       = {{Journal of Biological Chemistry}},
  title        = {{Retardation of Aβ42 fibril formation by apolipoprotein A-I and recombinant HDL particles}},
  url          = {{http://dx.doi.org/10.1016/j.jbc.2023.105273}},
  doi          = {{10.1016/j.jbc.2023.105273}},
  volume       = {{299}},
  year         = {{2023}},
}