Investigating how changes in the levels of kinesins impact neuronal health in <i>Drosophila</i> and human iPSC-derived neurons AD model

Alzheimer's disease (AD) is the leading cause of dementia and the most common neurodegenerative disorder. Understanding the molecular pathology of AD 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 in Drosophila. We find that Aβ42Arc flies present aberrant neurons, with altered axonal transport of mitochondria and aberrant terminal boutons at neuromuscular junctions. We demonstrate that the motor proteins kinesin-1 and kinesin-3 are essential for the correct development of neurons in Drosophila larvae and in human induced pluripotent stem cell-derived cortical neurons. We then show that the overexpression of kinesin-1 or kinesin-3 restores the correct number and morphology of boutons in Aβ42Arc-expressing neurons and rescues neuronal function measured by negative geotaxis locomotor behavioural assay. We therefore provide new evidence towards understanding the mechanisms of axonal transport defects in AD, and our results support the idea that kinesins should be considered as potential drug targets to help reduce dementia-associated disorders.

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Publication Details

Journal
Open Biology
Published
2026-05-13
DOI
https://doi.org/10.1098/rsob.250319
Primary Topic
Microtubule and mitosis dynamics
Type
article
Field-Weighted Citation Impact
0.00

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article

Investigating how changes in the levels of kinesins impact neuronal health in Drosophila and human iPSC-derived neurons AD model

Deepthy Francis, Isabel M. Palacios, Francesco Paonessa, Isabel Peset et al.
Open Biology
Microtubule and mitosis dynamics
article

Investigating how changes in the levels of kinesins impact neuronal health in Drosophila and human iPSC-derived neurons AD model

Deepthy Francis, Isabel M. Palacios, Francesco Paonessa, Isabel Peset, Alexander J. Whitworth, Victoria L. Hewitt, Maria Southall, Caroline C. G. Fabre, Frederick J. Livesey
article en

Abstract

Alzheimer's disease (AD) is the leading cause of dementia and the most common neurodegenerative disorder. Understanding the molecular pathology of AD 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 in Drosophila. We find that Aβ42Arc flies present aberrant neurons, with altered axonal transport of mitochondria and aberrant terminal boutons at neuromuscular junctions. We demonstrate that the motor proteins kinesin-1 and kinesin-3 are essential for the correct development of neurons in Drosophila larvae and in human induced pluripotent stem cell-derived cortical neurons. We then show that the overexpression of kinesin-1 or kinesin-3 restores the correct number and morphology of boutons in Aβ42Arc-expressing neurons and rescues neuronal function measured by negative geotaxis locomotor behavioural assay. We therefore provide new evidence towards understanding the mechanisms of axonal transport defects in AD, and our results support the idea that kinesins should be considered as potential drug targets to help reduce dementia-associated disorders.

Open BiologyVol. 16(5)
Royal Society of Medicine (GB), Royal Society (GB), Centre National de la Recherche Scientifique (FR), Talisman Energy (GB), University of Auckland (NZ), Queen Mary University of London (GB), Université Paris-Est Créteil (FR), Université Paris Cité (FR), University of Cambridge (GB), Royal Society of Chemistry (GB), Sorbonne Université (FR), Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR), Spanish National Cancer Research Centre (ES), Sorbonne Paris Cité (FR), Bridge University (SS), Gilead Sciences (Canada) (CA), Gilead Sciences (United Kingdom) (GB), Gilead Sciences (Spain) (ES), Institut d'écologie et des sciences de l'environnement de Paris (FR), Gilead Sciences (United States) (US), Gilead Sciences (Australia) (AU), Institut de Recherche pour le Développement (FR), Université Paris 8 (FR), MRC Mitochondrial Biology Unit (GB)
Queen Mary University of London, Wellcome Trust, Alzheimer's Research Trust, European Commission, Isaac Newton Trust, Biotechnology and Biological Sciences Research Council
Good health and well-being
Openalex Percentile: Top 9%
Microtubule and mitosis dynamics
DOIOpen Access PDFOpenAlex
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