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pGluAβ increases accumulation of Aβ in vivo and exacerbates its toxicity

Sofola-Adesakin, O; Khericha, M; Snoeren, I; Tsuda, L; Partridge, L; (2016) pGluAβ increases accumulation of Aβ in vivo and exacerbates its toxicity. Acta Neuropathologica Communications , 4 , Article 109. 10.1186/s40478-016-0380-x. Green open access

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Abstract

Several species of β-amyloid peptides (Aβ) exist as a result of differential cleavage from amyloid precursor protein (APP) to yield various C-terminal Aβ peptides. Several N-terminal modified Aβ peptides have also been identified in Alzheimer’s disease (AD) brains, the most common of which is pyroglutamate-modified Aβ (AβpE3-42). AβpE3-42 peptide has an increased propensity to aggregate, appears to accumulate in the brain before the appearance of clinical symptoms of AD, and precedes Aβ1-42 deposition. Moreover, in vitro studies have shown that AβpE3-42 can act as a seed for full length Aβ1-42. In this study, we characterized the Drosophila model of AβpE3-42 toxicity by expressing the peptide in specific sets of neurons using the GAL4-UAS system, and measuring different phenotypic outcomes. We found that AβpE3-42 peptide had an increased propensity to aggregate. Expression of AβpE3-42 in the neurons of adult flies led to behavioural dysfunction and shortened lifespan. Expression of AβpE3-42 constitutively in the eyes led to disorganised ommatidia, and activation of the c-Jun N-terminal kinase (JNK) signaling pathway. The eye disruption was almost completely rescued by co-expressing a candidate Aβ degrading enzyme, neprilysin2. Furthermore, we found that neprilysin2 was capable of degrading AβpE3-42. Also, we tested the seeding hypothesis for AβpE3-42 in vivo, and measured its effect on Aβ1-42 levels. We found that Aβ1-42 levels were significantly increased when Aβ1-42 and AβpE3-42 peptides were co-expressed. Furthermore, we found that AβpE3-42 enhanced Aβ1-42 toxicity in vivo. Our findings implicate AβpE3-42 as an important source of toxicity in AD, and suggest that its specific degradation could be therapeutic.

Type: Article
Title: pGluAβ increases accumulation of Aβ in vivo and exacerbates its toxicity
Open access status: An open access version is available from UCL Discovery
DOI: 10.1186/s40478-016-0380-x
Publisher version: http://dx.doi.org/10.1186/s40478-016-0380-x
Language: English
Additional information: Copyright © The Author(s) 2016. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Keywords: Neurodegeneration, Alzheimer’s disease, pyroglutamate Abeta, Drosophila
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment
URI: https://discovery.ucl.ac.uk/id/eprint/1522072
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