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Levels of kinesin light chain and dynein intermediate chain are reduced in the frontal cortex in Alzheimer’s disease: implications for axoplasmic transport

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Abstract

Fast anterograde and retrograde axoplasmic transports in neurons rely on the activity of molecular motors and are critical for maintenance of neuronal and synaptic functions. Disturbances of axoplasmic transport have been identified in Alzheimer’s disease and in animal models of this disease, but their mechanisms are not well understood. In this study we have investigated the distribution and the level of expression of kinesin light chains (KLCs) (responsible for binding of cargos during anterograde transport) and of dynein intermediate chain (DIC) (a component of the dynein complex during retrograde transport) in frontal cortex and cerebellar cortex of control subjects and Alzheimer’s disease patients. By immunoblotting, we found a significant decrease in the levels of expression of KLC1 and 2 and DIC in the frontal cortex, but not in the cerebellar cortex, of Alzheimer’s disease patients. A significant decrease in the levels of synaptophysin and of tubulin-β3 proteins, two neuronal markers, was also observed. KLC1 and DIC immunoreactivities did not co-localize with neurofibrillary tangles. The mean mRNA levels of KLC1, 2 and DIC were not significantly different between controls and AD patients. In SH-SY5Y neural cells, GSK-3β phosphorylated KLC1, a change associated to decreased association of KLC1 with its cargoes. Increased levels of active GSK-3β and of phosphorylated KLC1 were also observed in AD frontal cortex. We suggest that reduction of KLCs and DIC proteins in AD cortex results from both reduced expression and neuronal loss, and that these reductions and GSK-3β-mediated phosphorylation of KLC1 contribute to disturbances of axoplasmic flows and synaptic integrity in Alzheimer’s disease.

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Acknowledgments

This study was supported by the Interuniversity Attraction Poles program (P6/43) of the Belgian Federal Science Policy Office (BELSPO), by the Diane program (Walloon region), by grants from the Fonds de la Recherche Scientifique Médicale, and the Fondation pour la Recherche sur la maladie d’Alzheimer/Stichting voor Alzheimer Onderzoek. M. Morel was supported by a grant from the Van Buuren Foundation. The authors thank Dr Doble (Mc Master University, Canada) for providing the GSK-3β-K85A construct.

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  1. Laboratory of Histology, Neuroanatomy and Neuropathology, Faculty of Medicine, Université Libre de Bruxelles, 808, Route de Lennik, Bldg GE, 1070, Brussels, Belgium

    Marina Morel, Céline Héraud, Charles Nicaise, Valérie Suain & Jean-Pierre Brion

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  1. Marina Morel
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Correspondence to Jean-Pierre Brion.

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401_2011_901_MOESM1_ESM.eps

Supplementary Figure S1: Detection of PHF-tau proteins in subjects used in this study. (a and b): Immunoblots of homogenates of the frontal cortex in control subjects (a) and in AD patients (b) with an anti-phosphotau antibody (PHF-1). Three main bands between 50 kD and 70 kD (PHF-tau proteins) were observed in AD frontal cortex. Control cases did not show these PHF-1 positive bands with the exception of one case (Fig. 1a, line 4) showing faintly reactive PHF-1 bands. Numbers on the left of blots refer to the positions of molecular weight markers: 36kD (Carbonic anhydrase), 50kD (alcohol dehydrogenase), 64kD (glutamic dehydrogenase), 98kD (BSA). (EPS 3,174 kb)

401_2011_901_MOESM2_ESM.eps

Supplementary Figure S2: Absence of phosphosensitivity of the KLC1 antibody. Homogenates of frontal cortex of the same subjects were treated (b) or not (a) with lambda phosphatase before immunoblotting with the anti-KLC1 antibody. Lanes 1 and 2: control subject. Lanes 3 and 4: AD patient. Prior dephosphorylation did not affect the level of labeling of KLC1 with the anti-KLC1 antibody. (EPS 4,080 kb)

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Morel, M., Héraud, C., Nicaise, C. et al. Levels of kinesin light chain and dynein intermediate chain are reduced in the frontal cortex in Alzheimer’s disease: implications for axoplasmic transport. Acta Neuropathol 123, 71–84 (2012). https://doi.org/10.1007/s00401-011-0901-4

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