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Swedish Alzheimer's disease variant perturbs activity of retrograde molecular motors and causes widespread derangement of axonal transport pathways

M. Feole, VM. Pozo Devoto, N. Dragišić, C. Arnaiz, J. Bianchelli, K. Texlová, K. Kovačovicova, JS. Novotny, D. Havas, TL. Falzone, GB. Stokin

. 2024 ; 300 (4) : 107137. [pub] 20240305

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc24014452

Experimental studies in flies, mice, and humans suggest a significant role of impaired axonal transport in the pathogenesis of Alzheimer's disease (AD). The mechanisms underlying these impairments in axonal transport, however, remain poorly understood. Here we report that the Swedish familial AD mutation causes a standstill of the amyloid precursor protein (APP) in the axons at the expense of its reduced anterograde transport. The standstill reflects the perturbed directionality of the axonal transport of APP, which spends significantly more time traveling in the retrograde direction. This ineffective movement is accompanied by an enhanced association of dynactin-1 with APP, which suggests that reduced anterograde transport of APP is the result of enhanced activation of the retrograde molecular motor dynein by dynactin-1. The impact of the Swedish mutation on axonal transport is not limited to the APP vesicles since it also reverses the directionality of a subset of early endosomes, which become enlarged and aberrantly accumulate in distal locations. In addition, it also reduces the trafficking of lysosomes due to their less effective retrograde movement. Altogether, our experiments suggest a pivotal involvement of retrograde molecular motors and transport in the mechanisms underlying impaired axonal transport in AD and reveal significantly more widespread derangement of axonal transport pathways in the pathogenesis of AD.

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$a Feole, Monica $u Translational Ageing and Neuroscience Program, Centre for Translational Medicine, International Clinical Research Centre, St Anne's University Hospital, Brno, Czech Republic; Faculty of Medicine, Department of Biology, Masaryk University, Brno, Czech Republic; School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London, UK
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$a Swedish Alzheimer's disease variant perturbs activity of retrograde molecular motors and causes widespread derangement of axonal transport pathways / $c M. Feole, VM. Pozo Devoto, N. Dragišić, C. Arnaiz, J. Bianchelli, K. Texlová, K. Kovačovicova, JS. Novotny, D. Havas, TL. Falzone, GB. Stokin
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$a Experimental studies in flies, mice, and humans suggest a significant role of impaired axonal transport in the pathogenesis of Alzheimer's disease (AD). The mechanisms underlying these impairments in axonal transport, however, remain poorly understood. Here we report that the Swedish familial AD mutation causes a standstill of the amyloid precursor protein (APP) in the axons at the expense of its reduced anterograde transport. The standstill reflects the perturbed directionality of the axonal transport of APP, which spends significantly more time traveling in the retrograde direction. This ineffective movement is accompanied by an enhanced association of dynactin-1 with APP, which suggests that reduced anterograde transport of APP is the result of enhanced activation of the retrograde molecular motor dynein by dynactin-1. The impact of the Swedish mutation on axonal transport is not limited to the APP vesicles since it also reverses the directionality of a subset of early endosomes, which become enlarged and aberrantly accumulate in distal locations. In addition, it also reduces the trafficking of lysosomes due to their less effective retrograde movement. Altogether, our experiments suggest a pivotal involvement of retrograde molecular motors and transport in the mechanisms underlying impaired axonal transport in AD and reveal significantly more widespread derangement of axonal transport pathways in the pathogenesis of AD.
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$a Pozo Devoto, Victorio M $u Translational Ageing and Neuroscience Program, Centre for Translational Medicine, International Clinical Research Centre, St Anne's University Hospital, Brno, Czech Republic
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$a Dragišić, Neda $u Translational Ageing and Neuroscience Program, Centre for Translational Medicine, International Clinical Research Centre, St Anne's University Hospital, Brno, Czech Republic
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