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Dopamine-depletion and increased α-synuclein load induce degeneration of cortical cholinergic fibers in mice

  • Éva M. Szegő
    Correspondence
    Corresponding author at: Department of NeuroDegeneration and Restorative Research, Georg-August University; DFG Research Center for Molecular Physiology of the Brain (CMPB), Göttingen, Waldweg 33, D-37073, Germany. Tel.: +49 551 3913547; fax: +49 551 3913541.
    Affiliations
    Department of NeuroDegeneration and Restorative Research, Georg-August University, DFG Research Center: Molecular Physiology of the Brain (CMPB), Göttingen, 37073, Germany
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  • Ellen Gerhardt
    Affiliations
    Department of NeuroDegeneration and Restorative Research, Georg-August University, DFG Research Center: Molecular Physiology of the Brain (CMPB), Göttingen, 37073, Germany
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  • Tiago F. Outeiro
    Affiliations
    Department of NeuroDegeneration and Restorative Research, Georg-August University, DFG Research Center: Molecular Physiology of the Brain (CMPB), Göttingen, 37073, Germany
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  • Pawel Kermer
    Affiliations
    Department of NeuroDegeneration and Restorative Research, Georg-August University, DFG Research Center: Molecular Physiology of the Brain (CMPB), Göttingen, 37073, Germany

    Department of Neurology, Georg-August University, DFG Research Center: Molecular Physiology of the Brain (CMPB), Göttingen, 37073, Germany
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      Abstract

      Cognitive dysfunction can be common among Parkinson's disease (PD) patients, and multiplication of the gene α-synuclein (αsyn) increases the risk of dementia. Here, we studied the role of dopamine-depletion and increased αsyn load and aggregation on cholinergic structures in vivo. Wild-type (WT) and mice with A30P αsyn overexpression were treated subacutely with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and the number of cholinergic cells in their nucleus basalis magnocellularis-substantia innominata (NBM-SI), their cortical fiber density and their expression of different genes 1 day or 90 days after the last MPTP-injection were measured. Long-term dopamine depletion decreased the expression of choline acetyl transferase (ChAT) in the NBM-SI of WT mice, but no neuron loss was observed. In contrast, cortical cholinergic fiber density was decreased three months after MPTP-injection. Increased brain-derived neurotrophic factor expression could maintain cholinergic functions under these conditions. Expression of A30P αsyn in six-months-old transgenic mice resulted in decreased tyrosine receptor kinase B expression, and lower cortical cholinergic fiber density. Dopamine-depletion by MPTP induced cholinergic cell loss in the NBM-SI and increased cortical fiber loss. Our findings may explain why cholinergic cells are more vulnerable in PD, leading to an increased probability of dementia.

      Keywords

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