Cellular polyamines promote amyloid-beta (Aβ) peptide fibrillation and modulate the aggregation pathways
Luo, Jinghui ; Yu, Chien-Hung ; Yu, Huixin ; Borstnar, Rok ; Kamerlin, Shina C L LU
; Gräslund, Astrid
; Abrahams, Jan Pieter
and Wärmländer, Sebastian K T S
(2013)
In ACS Chemical Neuroscience
4(3).
p.62-454
- Abstract
The cellular polyamines spermine, spermidine, and their metabolic precursor putrescine, have long been associated with cell-growth, tumor-related gene regulations, and Alzheimer's disease. Here, we show by in vitro spectroscopy and AFM imaging, that these molecules promote aggregation of amyloid-beta (Aβ) peptides into fibrils and modulate the aggregation pathways. NMR measurements showed that the three polyamines share a similar binding mode to monomeric Aβ(1-40) peptide. Kinetic ThT studies showed that already very low polyamine concentrations promote amyloid formation: addition of 10 μM spermine (normal intracellular concentration is ~1 mM) significantly decreased the lag and transition times of the aggregation process. Spermidine... (More)
The cellular polyamines spermine, spermidine, and their metabolic precursor putrescine, have long been associated with cell-growth, tumor-related gene regulations, and Alzheimer's disease. Here, we show by in vitro spectroscopy and AFM imaging, that these molecules promote aggregation of amyloid-beta (Aβ) peptides into fibrils and modulate the aggregation pathways. NMR measurements showed that the three polyamines share a similar binding mode to monomeric Aβ(1-40) peptide. Kinetic ThT studies showed that already very low polyamine concentrations promote amyloid formation: addition of 10 μM spermine (normal intracellular concentration is ~1 mM) significantly decreased the lag and transition times of the aggregation process. Spermidine and putrescine additions yielded similar but weaker effects. CD measurements demonstrated that the three polyamines induce different aggregation pathways, involving different forms of induced secondary structure. This is supported by AFM images showing that the three polyamines induce Aβ(1-40) aggregates with different morphologies. The results reinforce the notion that designing suitable ligands which modulate the aggregation of Aβ peptides toward minimally toxic pathways may be a possible therapeutic strategy for Alzheimer's disease.
(Less)
- author
- Luo, Jinghui
; Yu, Chien-Hung
; Yu, Huixin
; Borstnar, Rok
; Kamerlin, Shina C L
LU
; Gräslund, Astrid
; Abrahams, Jan Pieter
and Wärmländer, Sebastian K T S
- publishing date
- 2013-03-20
- type
- Contribution to journal
- publication status
- published
- keywords
- Alzheimer Disease/metabolism, Amyloid/metabolism, Amyloid beta-Peptides/chemistry, Humans, Peptide Fragments/chemistry, Polyamines/chemistry, Putrescine/chemistry, Signal Transduction/physiology, Spermidine/chemistry, Spermine/chemistry
- in
- ACS Chemical Neuroscience
- volume
- 4
- issue
- 3
- pages
- 9 pages
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- scopus:84875502892
- pmid:23509981
- ISSN
- 1948-7193
- DOI
- 10.1021/cn300170x
- language
- English
- LU publication?
- no
- id
- b7578971-f5aa-4c13-8ffb-ecaa7df6496b
- date added to LUP
- 2025-01-11 22:03:17
- date last changed
- 2025-06-29 18:19:05
@article{b7578971-f5aa-4c13-8ffb-ecaa7df6496b,
abstract = {{<p>The cellular polyamines spermine, spermidine, and their metabolic precursor putrescine, have long been associated with cell-growth, tumor-related gene regulations, and Alzheimer's disease. Here, we show by in vitro spectroscopy and AFM imaging, that these molecules promote aggregation of amyloid-beta (Aβ) peptides into fibrils and modulate the aggregation pathways. NMR measurements showed that the three polyamines share a similar binding mode to monomeric Aβ(1-40) peptide. Kinetic ThT studies showed that already very low polyamine concentrations promote amyloid formation: addition of 10 μM spermine (normal intracellular concentration is ~1 mM) significantly decreased the lag and transition times of the aggregation process. Spermidine and putrescine additions yielded similar but weaker effects. CD measurements demonstrated that the three polyamines induce different aggregation pathways, involving different forms of induced secondary structure. This is supported by AFM images showing that the three polyamines induce Aβ(1-40) aggregates with different morphologies. The results reinforce the notion that designing suitable ligands which modulate the aggregation of Aβ peptides toward minimally toxic pathways may be a possible therapeutic strategy for Alzheimer's disease.</p>}},
author = {{Luo, Jinghui and Yu, Chien-Hung and Yu, Huixin and Borstnar, Rok and Kamerlin, Shina C L and Gräslund, Astrid and Abrahams, Jan Pieter and Wärmländer, Sebastian K T S}},
issn = {{1948-7193}},
keywords = {{Alzheimer Disease/metabolism; Amyloid/metabolism; Amyloid beta-Peptides/chemistry; Humans; Peptide Fragments/chemistry; Polyamines/chemistry; Putrescine/chemistry; Signal Transduction/physiology; Spermidine/chemistry; Spermine/chemistry}},
language = {{eng}},
month = {{03}},
number = {{3}},
pages = {{62--454}},
publisher = {{The American Chemical Society (ACS)}},
series = {{ACS Chemical Neuroscience}},
title = {{Cellular polyamines promote amyloid-beta (Aβ) peptide fibrillation and modulate the aggregation pathways}},
url = {{http://dx.doi.org/10.1021/cn300170x}},
doi = {{10.1021/cn300170x}},
volume = {{4}},
year = {{2013}},
}