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Mechanism of amyloid protein aggregation and the role of inhibitors

Linse, Sara LU (2019) In Pure and Applied Chemistry 91(2). p.211-229
Abstract

Inhibition of amyloid β peptide (Aβ) aggregation is an important goal due to the connection of this process with Alzheimer's disease. Traditionally, inhibitors were developed with an aim to retard the overall macroscopic aggregation. However, recent advances imply that approaches based on mechanistic insights may be more powerful. In such approaches, the microscopic steps underlying the aggregation process are identified, and it is established which of these step(s) lead to neurotoxicity. Inhibitors are then derived to specifically target steps involved in toxicity. The Aβ aggregation process is composed of at minimum three microscopic steps: primary nucleation of monomers only, secondary nucleation of monomers on fibril surface, and... (More)

Inhibition of amyloid β peptide (Aβ) aggregation is an important goal due to the connection of this process with Alzheimer's disease. Traditionally, inhibitors were developed with an aim to retard the overall macroscopic aggregation. However, recent advances imply that approaches based on mechanistic insights may be more powerful. In such approaches, the microscopic steps underlying the aggregation process are identified, and it is established which of these step(s) lead to neurotoxicity. Inhibitors are then derived to specifically target steps involved in toxicity. The Aβ aggregation process is composed of at minimum three microscopic steps: primary nucleation of monomers only, secondary nucleation of monomers on fibril surface, and elongation of fibrils by monomer addition. The vast majority of toxic species are generated from the secondary nucleation process: this may be a key process to inhibit in order to limit toxicity. Inhibition of primary nucleation, which delays the emergence of toxic species without affecting their total concentration, may also be effective. Inhibition of elongation may instead increase the toxicity over time. Here we briefly review findings regarding secondary nucleation of Aβ, its dominance over primary nucleation, and attempts to derive inhibitors that specifically target secondary nucleation with an aim to limit toxicity.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
aggregation mechanism, Distinguished Women in Chemistry and Chemical Engineering, inhibitor design, self-assembly
in
Pure and Applied Chemistry
volume
91
issue
2
pages
19 pages
publisher
IUPAC
external identifiers
  • scopus:85061387231
ISSN
0033-4545
DOI
10.1515/pac-2018-1017
language
English
LU publication?
yes
id
a4c7e1f7-5486-4f4b-94de-35841c2e2ff7
date added to LUP
2019-02-19 10:29:12
date last changed
2020-02-26 07:16:31
@article{a4c7e1f7-5486-4f4b-94de-35841c2e2ff7,
  abstract     = {<p>Inhibition of amyloid β peptide (Aβ) aggregation is an important goal due to the connection of this process with Alzheimer's disease. Traditionally, inhibitors were developed with an aim to retard the overall macroscopic aggregation. However, recent advances imply that approaches based on mechanistic insights may be more powerful. In such approaches, the microscopic steps underlying the aggregation process are identified, and it is established which of these step(s) lead to neurotoxicity. Inhibitors are then derived to specifically target steps involved in toxicity. The Aβ aggregation process is composed of at minimum three microscopic steps: primary nucleation of monomers only, secondary nucleation of monomers on fibril surface, and elongation of fibrils by monomer addition. The vast majority of toxic species are generated from the secondary nucleation process: this may be a key process to inhibit in order to limit toxicity. Inhibition of primary nucleation, which delays the emergence of toxic species without affecting their total concentration, may also be effective. Inhibition of elongation may instead increase the toxicity over time. Here we briefly review findings regarding secondary nucleation of Aβ, its dominance over primary nucleation, and attempts to derive inhibitors that specifically target secondary nucleation with an aim to limit toxicity.</p>},
  author       = {Linse, Sara},
  issn         = {0033-4545},
  language     = {eng},
  number       = {2},
  pages        = {211--229},
  publisher    = {IUPAC},
  series       = {Pure and Applied Chemistry},
  title        = {Mechanism of amyloid protein aggregation and the role of inhibitors},
  url          = {http://dx.doi.org/10.1515/pac-2018-1017},
  doi          = {10.1515/pac-2018-1017},
  volume       = {91},
  year         = {2019},
}