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Title: Zinc-Amyloid Interactions on a Millisecond Time-Scale Stabilize Non-Fibrillar Alzheimer Related Species

Abstract

The role of zinc, an essential element for normal brain function, in the pathology of Alzheimer's disease (AD) is poorly understood. On one hand, physiological and genetic evidence from transgenic mouse models supports its pathogenic role in promoting the deposition of the amyloid {beta}-protein (A{beta}) in senile plaques. On the other hand, levels of extracellular ('free') zinc in the brain, as inferred by the levels of zinc in cerebrospinal fluid, were found to be too low for inducing A{beta} aggregation. Remarkably, the release of transient high local concentrations of zinc during rapid synaptic events was reported. The role of such free zinc pulses in promoting A{beta} aggregation has never been established. Using a range of time-resolved structural and spectroscopic techniques, we found that zinc, when introduced in millisecond pulses of micromolar concentrations, immediately interacts with A{beta} 1-40 and promotes its aggregation. These interactions specifically stabilize non-fibrillar pathogenic related aggregate forms and prevent the formation of A{beta} fibrils (more benign species) presumably by interfering with the self-assembly process of A{beta}. These in vitro results strongly suggest a significant role for zinc pulses in A{beta} pathology. We further propose that by interfering with A{beta} self-assembly, which leads to insoluble, non-pathological fibrillar forms,more » zinc stabilizes transient, harmful amyloid forms. This report argues that zinc represents a class of molecular pathogens that effectively perturb the self-assembly of benign A{beta} fibrils, and stabilize harmful non-fibrillar forms.« less

Authors:
; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Lab. (BNL), Upton, NY (United States). National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
959783
Report Number(s):
BNL-82769-2009-JA
Journal ID: ISSN 0002-7863; JACSAT; TRN: US201016%%927
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Journal Name:
Journal of the American Chemical Society
Additional Journal Information:
Journal Volume: 130; Journal ID: ISSN 0002-7863
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; BRAIN; CEREBROSPINAL FLUID; DEPOSITION; DISEASES; GENETICS; IN VITRO; PATHOGENS; PATHOLOGY; TRANSIENTS; ZINC; national synchrotron light source

Citation Formats

Noy, D, Solomonov, I, Sinkevich, O, Arad, A, Kjaer, K, and Sagi, I. Zinc-Amyloid Interactions on a Millisecond Time-Scale Stabilize Non-Fibrillar Alzheimer Related Species. United States: N. p., 2008. Web. doi:10.1021/ja076282l.
Noy, D, Solomonov, I, Sinkevich, O, Arad, A, Kjaer, K, & Sagi, I. Zinc-Amyloid Interactions on a Millisecond Time-Scale Stabilize Non-Fibrillar Alzheimer Related Species. United States. https://doi.org/10.1021/ja076282l
Noy, D, Solomonov, I, Sinkevich, O, Arad, A, Kjaer, K, and Sagi, I. 2008. "Zinc-Amyloid Interactions on a Millisecond Time-Scale Stabilize Non-Fibrillar Alzheimer Related Species". United States. https://doi.org/10.1021/ja076282l.
@article{osti_959783,
title = {Zinc-Amyloid Interactions on a Millisecond Time-Scale Stabilize Non-Fibrillar Alzheimer Related Species},
author = {Noy, D and Solomonov, I and Sinkevich, O and Arad, A and Kjaer, K and Sagi, I},
abstractNote = {The role of zinc, an essential element for normal brain function, in the pathology of Alzheimer's disease (AD) is poorly understood. On one hand, physiological and genetic evidence from transgenic mouse models supports its pathogenic role in promoting the deposition of the amyloid {beta}-protein (A{beta}) in senile plaques. On the other hand, levels of extracellular ('free') zinc in the brain, as inferred by the levels of zinc in cerebrospinal fluid, were found to be too low for inducing A{beta} aggregation. Remarkably, the release of transient high local concentrations of zinc during rapid synaptic events was reported. The role of such free zinc pulses in promoting A{beta} aggregation has never been established. Using a range of time-resolved structural and spectroscopic techniques, we found that zinc, when introduced in millisecond pulses of micromolar concentrations, immediately interacts with A{beta} 1-40 and promotes its aggregation. These interactions specifically stabilize non-fibrillar pathogenic related aggregate forms and prevent the formation of A{beta} fibrils (more benign species) presumably by interfering with the self-assembly process of A{beta}. These in vitro results strongly suggest a significant role for zinc pulses in A{beta} pathology. We further propose that by interfering with A{beta} self-assembly, which leads to insoluble, non-pathological fibrillar forms, zinc stabilizes transient, harmful amyloid forms. This report argues that zinc represents a class of molecular pathogens that effectively perturb the self-assembly of benign A{beta} fibrils, and stabilize harmful non-fibrillar forms.},
doi = {10.1021/ja076282l},
url = {https://www.osti.gov/biblio/959783}, journal = {Journal of the American Chemical Society},
issn = {0002-7863},
number = ,
volume = 130,
place = {United States},
year = {Tue Jan 01 00:00:00 EST 2008},
month = {Tue Jan 01 00:00:00 EST 2008}
}