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Neurotoxicity of Alzheimer's disease A? peptides is induced by small changes in the A?42 to A?40 ratio.

ABSTRACT: The amyloid peptides A?(40) and A?(42) of Alzheimer's disease are thought to contribute differentially to the disease process. Although A?(42) seems more pathogenic than A?(40), the reason for this is not well understood. We show here that small alterations in the A?(42):A?(40) ratio dramatically affect the biophysical and biological properties of the A? mixtures reflected in their aggregation kinetics, the morphology of the resulting amyloid fibrils and synaptic function tested in vitro and in vivo. A minor increase in the A?(42):A?(40) ratio stabilizes toxic oligomeric species with intermediate conformations. The initial toxic impact of these A? species is synaptic in nature, but this can spread into the cells leading to neuronal cell death. The fact that the relative ratio of A? peptides is more crucial than the absolute amounts of peptides for the induction of neurotoxic conformations has important implications for anti-amyloid therapy. Our work also suggests the dynamic nature of the equilibrium between toxic and non-toxic intermediates.

SUBMITTER: Kuperstein I

PROVIDER: S-EPMC2957213 | biostudies-other | 2010 Oct

REPOSITORIES: biostudies-other

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Neurotoxicity of Alzheimer's disease Aβ peptides is induced by small changes in the Aβ42 to Aβ40 ratio.

Kuperstein Inna I Broersen Kerensa K Benilova Iryna I Rozenski Jef J Jonckheere Wim W Debulpaep Maja M Vandersteen Annelies A Segers-Nolten Ine I Van Der Werf Kees K Subramaniam Vinod V Braeken Dries D Callewaert Geert G Bartic Carmen C D'Hooge Rudi R Martins Ivo Cristiano IC Rousseau Frederic F Schymkowitz Joost J De Strooper Bart B

The EMBO journal 20100903 19

The amyloid peptides Aβ(40) and Aβ(42) of Alzheimer's disease are thought to contribute differentially to the disease process. Although Aβ(42) seems more pathogenic than Aβ(40), the reason for this is not well understood. We show here that small alterations in the Aβ(42):Aβ(40) ratio dramatically affect the biophysical and biological properties of the Aβ mixtures reflected in their aggregation kinetics, the morphology of the resulting amyloid fibrils and synaptic function tested in vitro and in ...[more]

PMID: 20818335

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Project description:Amyloid-beta (A?) is produced by the cleavage of amyloid precursor proteins in the cell membrane by ?-secretase and ?-secretase into a monomeric form with peptides of different lengths such as A?1-40 or A?1-42, which is then transformed into oligomeric and fibril forms and is considered to be one of the hallmarks of Alzheimer's disease (AD). The plasma concentrations of A?1-40 and A?1-42 are unstable after blood samples have been obtained. In order to examine the dynamic changes of plasma A?1-42 and A?1-40 in blood samples, we used fresh blood samples in ethylenediaminetetraacetic acid tubes from 32 clinically diagnosed AD patients. Each sample was subdivided into eight sub-samples, and levels of A?1-40 and A?1-42 were measured at 0 (baseline), 0.5, 1, 2, 3, 5, 8, and 24 h, respectively. All samples were incubated at 37°C before being measuring. The results showed that compared to baseline, 87.5 and 62.5% of the patients had higher plasma levels of A?1-42 and A?1-40 at 24 h, respectively. The patients with an increased amyloid level did not have a significantly different apo-lipoprotein E4 allele (APOE4) gene status for either A?1-40 (p = 0.422) or A?1-42 (p = 1.000). However, for plasma A?1-42, the APOE4 carriers had a significantly lower level than the non-carriers at baseline [31.2 ± 6.5 (mean ± SD) ng/ml vs. 50.4 ± 47.7 ng/ml, p = 0.031] and 0.5 h (37.5 ± 7.6 ng/ml vs. 51.9 ± 30.8 ng/ml, p = 0.043). There were no significant differences between the APOE4 carriers and non-carriers in plasma A?1-42 concentration at 1, 2, 3, 5, 8, and 24 h (p = 0.112, p = 0.086, p = 0.112, p = 0.263, p = 0.170 and p = 0.621, respectively). The A?1-40 level was related to disease severity as assessed using the clinical dementia rating (CDR) scale. Patients with advanced stages of dementia (CDR = 1 and CDR = 2) had a significantly higher A?1-40 level compared to those with very mild stage dementia (CDR = 0.5) at all time points (p < 0.05) except for 24 h (p = 0.059). Our findings illustrate the effects of APOE4 status on dynamic changes in plasma A?1-40 and A?1-42 levels, and significant associations between A?1-40 level and disease severity. Further studies are needed to investigate the exact mechanisms of how APOE4 affects the dynamic changes in plasma A?1-40 and A?1-42, and the association between A?1-40 and advanced dementia.

Dataset Information

Neurotoxicity of Alzheimer's disease A? peptides is induced by small changes in the A?42 to A?40 ratio.

Publications

Neurotoxicity of Alzheimer's disease Aβ peptides is induced by small changes in the Aβ42 to Aβ40 ratio.

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