Journal Article

FZJ-2021-00623

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The interaction of insoluble Amyloid‐β with soluble Amyloid‐β dimers decreases Amyloid‐β plaque numbers

Gerresheim, E. F. ; Herring, A. ; Gremer, L.FZJ* ; Müller‐Schiffmann, A. ; Keyvani, K. ; Korth, C. (Corresponding author)

2021
Wiley-Blackwell Oxford [u.a.]

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Please use a persistent id in citations: http://hdl.handle.net/2128/28413  doi:10.1111/nan.12685

Abstract: ObjectivesThe heterogeneity of Amyloid‐beta (Aβ) plaque load in patients with Alzheimer's disease (AD) has puzzled neuropathology. Since brain Aβ plaque load does not correlate with cognitive decline, neurotoxic soluble Aβ oligomers have been championed as disease‐causing agents in early AD. So far, investigating molecular interactions between soluble oligomeric Aβ and insoluble Aβ in vivo has been difficult because of the abundance of Aβ oligomer species and the kinetic equilibrium in which they coexist. Here, we investigated whether Aβ plaque heterogeneity relates to interactions of different Aβ conformers.Materials and MethodsWe took advantage of transgenic mice that generate exclusively Aβ dimers (tgDimer mice) but do not develop Aβ plaques or neuroinflammation during their lifetime, crossed them to the transgenic CRND8 mice that develop plaques after 90 days and measured Aβ plaque load using immunohistochemical and biochemical assays. Furthermore, we performed in vitro thioflavin T (ThT) aggregation assays titrating synthetic Aβ42‐S8C dimers into fibril‐forming synthetic Aβ42.ResultsWe observed a lower number of Aβ plaques in the brain of double transgenic mice compared to tgCRND8 mice alone while the average plaque size remained unaltered. Corroborating these in vivo findings, synthetic Aβ‐S8C dimers inhibited fibril formation of wild‐type Aβ also in vitro, seen by an increased half‐time in the ThT assay.ConclusionsOur study indicates that Aβ dimers directly interfere with Aβ fibril formation in vivo and in vitro. The variable interaction of Aβ dimers with insoluble Aβ seeds could thus contribute to the heterogeneity of Aβ plaque load in AD patients.

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Contributing Institute(s):

1. Strukturbiochemie (IBI-7)

Research Program(s):

1. 5244 - Information Processing in Neuronal Networks (POF4-524) (POF4-524)

Appears in the scientific report 2021

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