Essential conserved neuronal motors kinesin-1 and kinesin-3 regulate Aβ42 toxicity in vivo
Alzheimer’s Disease is the leading cause of dementia and the most common neurodegenerative disorder. Understanding the molecular pathology of Alzheimer’s Disease may help identify new ways to reduce neuronal damage. In the past decades Drosophila has become a powerful tool in modelling mechanisms un...
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ftqueenmaryuniv:oai:qmro.qmul.ac.uk:123456789/96768 2024-06-09T07:44:14+00:00 Essential conserved neuronal motors kinesin-1 and kinesin-3 regulate Aβ42 toxicity in vivo Palacios, IM Palacios De Castro, MI biorxiv team 2024-04-24 https://qmro.qmul.ac.uk/xmlui/handle/123456789/96768 https://doi.org/10.1101/2024.04.23.590704 unknown bioRxiv bioRxiv journal https://qmro.qmul.ac.uk/xmlui/handle/123456789/96768 doi:10.1101/2024.04.23.590704 Alzheimer’s Disease amyloid beta neurodegeneration axonal transport motor proteins Drosophila neurons human neurons iPSC Article 2024 ftqueenmaryuniv https://doi.org/10.1101/2024.04.23.590704 2024-05-14T23:36:51Z Alzheimer’s Disease is the leading cause of dementia and the most common neurodegenerative disorder. Understanding the molecular pathology of Alzheimer’s Disease may help identify new ways to reduce neuronal damage. In the past decades Drosophila has become a powerful tool in modelling mechanisms underlying human diseases. Here we investigate how the expression of the human 42-residue β-amyloid (Aβ) carrying the E22G pathogenic “Arctic” mutation (Aβ42Arc) affects axonal health and behaviour of Drosophila. We find that Aβ42Arc flies present aberrant neurons, with altered axonal transport of mitochondrial and an increased number of terminal boutons at neuromuscular junctions. We demonstrate that the major axonal motor proteins kinesin-1 and kinesin-3 are essential for the correct development of neurons in Drosophila larvae and similar findings are replicated in human iPSC-derived cortical neurons. We then show that the over-expression of kinesin-1 or kinesin-3 restores the correct number of terminal boutons in Aβ42Arc expressing neurons and that this is associated with a rescue of the overall neuronal function, measured by negative geotaxis locomotor behavioural assay. We therefore provide new evidence in understanding the mechanisms of axonal transport defects in Alzheimer’s Disease, and our results indicate that kinesins should be considered as potential drug targets to help reduce dementia-associated disorders. Article in Journal/Newspaper Arctic Queen Mary University of London: Queen Mary Research Online (QMRO) Arctic |
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Queen Mary University of London: Queen Mary Research Online (QMRO) |
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topic |
Alzheimer’s Disease amyloid beta neurodegeneration axonal transport motor proteins Drosophila neurons human neurons iPSC |
spellingShingle |
Alzheimer’s Disease amyloid beta neurodegeneration axonal transport motor proteins Drosophila neurons human neurons iPSC Palacios, IM Palacios De Castro, MI Essential conserved neuronal motors kinesin-1 and kinesin-3 regulate Aβ42 toxicity in vivo |
topic_facet |
Alzheimer’s Disease amyloid beta neurodegeneration axonal transport motor proteins Drosophila neurons human neurons iPSC |
description |
Alzheimer’s Disease is the leading cause of dementia and the most common neurodegenerative disorder. Understanding the molecular pathology of Alzheimer’s Disease may help identify new ways to reduce neuronal damage. In the past decades Drosophila has become a powerful tool in modelling mechanisms underlying human diseases. Here we investigate how the expression of the human 42-residue β-amyloid (Aβ) carrying the E22G pathogenic “Arctic” mutation (Aβ42Arc) affects axonal health and behaviour of Drosophila. We find that Aβ42Arc flies present aberrant neurons, with altered axonal transport of mitochondrial and an increased number of terminal boutons at neuromuscular junctions. We demonstrate that the major axonal motor proteins kinesin-1 and kinesin-3 are essential for the correct development of neurons in Drosophila larvae and similar findings are replicated in human iPSC-derived cortical neurons. We then show that the over-expression of kinesin-1 or kinesin-3 restores the correct number of terminal boutons in Aβ42Arc expressing neurons and that this is associated with a rescue of the overall neuronal function, measured by negative geotaxis locomotor behavioural assay. We therefore provide new evidence in understanding the mechanisms of axonal transport defects in Alzheimer’s Disease, and our results indicate that kinesins should be considered as potential drug targets to help reduce dementia-associated disorders. |
author2 |
biorxiv team |
format |
Article in Journal/Newspaper |
author |
Palacios, IM Palacios De Castro, MI |
author_facet |
Palacios, IM Palacios De Castro, MI |
author_sort |
Palacios, IM |
title |
Essential conserved neuronal motors kinesin-1 and kinesin-3 regulate Aβ42 toxicity in vivo |
title_short |
Essential conserved neuronal motors kinesin-1 and kinesin-3 regulate Aβ42 toxicity in vivo |
title_full |
Essential conserved neuronal motors kinesin-1 and kinesin-3 regulate Aβ42 toxicity in vivo |
title_fullStr |
Essential conserved neuronal motors kinesin-1 and kinesin-3 regulate Aβ42 toxicity in vivo |
title_full_unstemmed |
Essential conserved neuronal motors kinesin-1 and kinesin-3 regulate Aβ42 toxicity in vivo |
title_sort |
essential conserved neuronal motors kinesin-1 and kinesin-3 regulate aβ42 toxicity in vivo |
publisher |
bioRxiv |
publishDate |
2024 |
url |
https://qmro.qmul.ac.uk/xmlui/handle/123456789/96768 https://doi.org/10.1101/2024.04.23.590704 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_relation |
bioRxiv journal https://qmro.qmul.ac.uk/xmlui/handle/123456789/96768 doi:10.1101/2024.04.23.590704 |
op_doi |
https://doi.org/10.1101/2024.04.23.590704 |
_version_ |
1801373017643679744 |