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.

Instituto de Investigación en Biomedicina de Buenos Aires Facultad de Medicina Universidad de Buenos Aires Buenos Aires Argentina

Instituto de Investigación en Biomedicina de Buenos Aires Partner Institute of the Max Planck Society Buenos Aires Argentina

PsychoGenics Paramus New Jersey USA

Translational Ageing and Neuroscience Program Centre for Translational Medicine International Clinical Research Centre St Anne's University Hospital Brno Czech Republic

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 and Sciences King's College London London UK

Translational Ageing and Neuroscience Program Centre for Translational Medicine International Clinical Research Centre St Anne's University Hospital Brno Czech Republic; Institute for Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacký University Olomouc Olomouc Czech Republic

Translational Ageing and Neuroscience Program Centre for Translational Medicine International Clinical Research Centre St Anne's University Hospital Brno Czech Republic; Institute for Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacký University Olomouc Olomouc Czech Republic; Division of Neurology University Medical Centre Ljubljana Slovenia; Department of Neurosciences Mayo Clinic Rochester Minnesota USA

Translational Ageing and Neuroscience Program Centre for Translational Medicine International Clinical Research Centre St Anne's University Hospital Brno Czech Republic; PsychoGenics Paramus New Jersey USA

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