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pGluAß increases accumulation of Aß in vivo and exacerbates its toxicity

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posted on 2023-06-09, 08:33 authored by Oyinkan Adesakin, Mobina Khericha, Inge Snoeren, Leo Tsuda, Lina Partridge
Several species of ß-amyloid peptides (Aß) exist as a result of differential cleavage from amyloid precursor protein (APP) to yield various C-terminal Aß peptides. Several N-terminal modified Aß peptides have also been identified in Alzheimer’s disease (AD) brains, the most common of which is pyroglutamate-modified Aß (AßpE3-42). AßpE3-42 peptide has an increased propensity to aggregate, appears to accumulate in the brain before the appearance of clinical symptoms of AD, and precedes Aß1-42 deposition. Moreover, in vitro studies have shown that AßpE3-42 can act as a seed for full length Aß1-42. In this study, we characterized the Drosophila model of AßpE3-42 toxicity by expressing the peptide in specific sets of neurons using the GAL4-UAS system, and measuring different phenotypic outcomes. We found that AßpE3-42 peptide had an increased propensity to aggregate. Expression of AßpE3-42 in the neurons of adult flies led to behavioural dysfunction and shortened lifespan. Expression of AßpE3-42 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 Aß degrading enzyme, neprilysin2. Furthermore, we found that neprilysin2 was capable of degrading AßpE3-42. Also, we tested the seeding hypothesis for AßpE3-42 in vivo, and measured its effect on Aß1-42 levels. We found that Aß1-42 levels were significantly increased when Aß1-42 and AßpE3-42 peptides were co-expressed. Furthermore, we found that AßpE3-42 enhanced Aß1-42 toxicity in vivo. Our findings implicate AßpE3-42 as an important source of toxicity in AD, and suggest that its specific degradation could be therapeutic

History

Publication status

  • Published

File Version

  • Published version

Journal

Acta Neuropathologica Communications

ISSN

2051-5960

Publisher

BioMed Central

Issue

109

Volume

4

Department affiliated with

  • Neuroscience Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2017-11-02

First Open Access (FOA) Date

2017-11-02

First Compliant Deposit (FCD) Date

2017-11-02

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