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Cadmium-induced cell death of basal forebrain cholinergic neurons mediated by muscarinic M1 receptor blockade, increase in GSK-3β enzyme, β-amyloid and tau protein levels

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Abstract

Cadmium is a neurotoxic compound which induces cognitive alterations similar to those produced by Alzheimer’s disease (AD). However, the mechanism through which cadmium induces this effect remains unknown. In this regard, we described in a previous work that cadmium blocks cholinergic transmission and induces a more pronounced cell death on cholinergic neurons from basal forebrain which is partially mediated by AChE overexpression. Degeneration of basal forebrain cholinergic neurons, as happens in AD, results in memory deficits attributable to the loss of cholinergic modulation of hippocampal synaptic circuits. Moreover, cadmium has been described to activate GSK-3β, induce Aβ protein production and tau filament formation, which have been related to a selective loss of basal forebrain cholinergic neurons and development of AD. The present study is aimed at researching the mechanisms of cell death induced by cadmium on basal forebrain cholinergic neurons. For this purpose, we evaluated, in SN56 cholinergic mourine septal cell line from basal forebrain region, the cadmium toxic effects on neuronal viability through muscarinic M1 receptor, AChE splice variants, GSK-3β enzyme, Aβ and tau proteins. This study proves that cadmium induces cell death on cholinergic neurons through blockade of M1 receptor, overexpression of AChE-S and GSK-3β, down-regulation of AChE-R and increase in Aβ and total and phosphorylated tau protein levels. Our present results provide new understanding of the mechanisms contributing to the harmful effects of cadmium on cholinergic neurons and suggest that cadmium could mediate these mechanisms by M1R blockade through AChE splices altered expression.

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Acknowledgments

The authors thank Miguel Capo and Margarita Lobo, Professors of Toxicology from Universidad Complutense de Madrid, for their counseling during the preparation of the present work.

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The authors declare that they have no conflict of interest.

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    Authors and Affiliations

    1. Departamento de Toxicología y Farmacología, Facultad de Veterinaria, Universidad Complutense de Madrid, Avda. Puerta de Hierro s/n, 28040, Madrid, Spain

      Javier del Pino

    2. Department of Toxicology and Legal Medicine, Medical School, Complutense University of Madrid, 28041, Madrid, Spain

      Gabriela Zeballos, María José Anadón, Paula Moyano & José Manuel García

    3. Department of Toxicology and Pharmacology, Veterinary School, Complutense University of Madrid, 28040, Madrid, Spain

      María Jesús Díaz & María Teresa Frejo

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    1. Javier del Pino
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    Correspondence to Javier del Pino.

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    Javier del Pino and Gabriela Zeballos have contributed equally to this work.

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    del Pino, J., Zeballos, G., Anadón, M.J. et al. Cadmium-induced cell death of basal forebrain cholinergic neurons mediated by muscarinic M1 receptor blockade, increase in GSK-3β enzyme, β-amyloid and tau protein levels. Arch Toxicol 90, 1081–1092 (2016). https://doi.org/10.1007/s00204-015-1540-7

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