title: pGluAβ increases accumulation of Aβ in vivo and exacerbates its toxicity.
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). AβpE3-42peptide has an increased propensity to aggregate, appears to accumulate in the brain before the appearance of clinical symptoms of AD, and precedes Aβ1-42deposition. Moreover, in vitro studies have shown that AβpE3-42can act as a seed for full length Aβ1-42.In this study, we characterized the Drosophila model of AβpE3-42toxicity by expressing the peptide in specific sets of neurons using the GAL4-UAS system, and measuring different phenotypic outcomes. We found that AβpE3-42peptide had an increased propensity to aggregate. Expression of AβpE3-42in the neurons of adult flies led to behavioural dysfunction and shortened lifespan. Expression of AβpE3-42constitutively 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 AβpE3-42in vivo, and measured its effect on Aβ1-42levels. We found that Aβ1-42levels were significantly increased when Aβ1-42and AβpE3-42peptides were co-expressed. Furthermore, we found that AβpE3-42enhanced Aβ1-42toxicity in vivo. Our findings implicate AβpE3-42as an important source of toxicity in AD, and suggest that its specific degradation could be therapeutic.
authors.affiliation: Institute of Healthy Ageing, and G.E.E., University College London, Darwin Building, Gower Street, London, WC1E 6BT, UK.
authors.forename: Oyinkan
authors.initials: O
authors.lastname: Sofola-Adesakin
authors.affiliation: Institute of Healthy Ageing, and G.E.E., University College London, Darwin Building, Gower Street, London, WC1E 6BT, UK.|Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Straße 9B, 50931, Cologne, Germany.
authors.forename: Mobina
authors.initials: M
authors.lastname: Khericha
authors.affiliation: Institute of Healthy Ageing, and G.E.E., University College London, Darwin Building, Gower Street, London, WC1E 6BT, UK.|Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Straße 9B, 50931, Cologne, Germany.
authors.forename: Inge
authors.initials: I
authors.lastname: Snoeren
authors.affiliation: Center for Development of Advanced Medicine for Dementia (CAMD), National Center for Geriatrics and Gerontology (NCGG), Obu, Aichi, Japan.
authors.forename: Leo
authors.initials: L
authors.lastname: Tsuda
authors.affiliation: Institute of Healthy Ageing, and G.E.E., University College London, Darwin Building, Gower Street, London, WC1E 6BT, UK. l.partridge@ucl.ac.uk.|Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Straße 9B, 50931, Cologne, Germany. l.partridge@ucl.ac.uk.
authors.forename: Linda
authors.initials: L
authors.lastname: Partridge
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D005123:Eye / Q000378:metabolism / Q000473:pathology; D005260:Female; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D009043:Motor Activity / Q000502:physiology; D015260:Neprilysin / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D055550:Protein Stability; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D029721:Drosophila Proteins; C557617:GAL4 protein, Drosophila; D010446:Peptide Fragments; D014157:Transcription Factors; C075222:amyloid beta-protein (1-42); C532271:amyloid beta-protein (3-42), pyroglutamyl(3)-; D048031:JNK Mitogen-Activated Protein Kinases; D015260:Neprilysin; C000620628:neprilysin 2, Drosophila
keywords: Alzheimer’s disease; Drosophila; Neurodegeneration; pyroglutamate Abeta