Affiliations: [a] Department of Psychiatry and Psychotherapy, University Clinic of General and Social Psychiatry, Innsbruck Medical University, Innsbruck, Austria | [b] Department of Medical Genetics, Molecular and Clinical Pharmacology, Division of Molecular and Cellular Pharmacology, Innsbruck Medical University, Innsbruck, Austria | [c] Department of Pharmacology, Innsbruck Medical University, Innsbruck, Austria | [d] JSW-CNS Research, Forschungslabor GmbH, Graz, Austria | [e] Institut für Pharmakologie und Toxikologie, Technische Universität München, München, Germany | [f] Department of Psychiatry, Landeskrankenhaus Rankweil, Rankweil, Austria
Correspondence:
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Correspondence to: Dr. Josef Marksteiner, Department of Psychiatry I, Valdunastraße 16 A-6830, Rankweil, Austria. E-mail: j.marksteiner@i-med.ac.at
Abstract: Cumulative evidence indicates that amyloid-β peptides exert some of their neurodegenerative effects through modulation of L-type voltage gated calcium channels, which play key roles in a diverse range of CNS functions. In this study we examined the expression of CaV1.2 L-type voltage gated calcium channels in transgenic mice overexpressing human AβPP751 with the London (V717I) and Swedish (K670M/N671L) mutations by immunohistochemistry in light and electron microscopy. In hippocampal layers of wild type and transgenic mice, CaV1.2 channels were predominantly localized to somato-dendritic domains of neurons, and to astrocytic profiles with an age-dependent increase in labeling density. In transgenic animals, CaV1.2-like immunoreactive clusters were found in neuronal profiles in association with amyloid-β plaques. Both the number and density of these clusters depended upon age of animals and number of plaques. The most striking difference between wild type and transgenic mice was the age-dependent expression of CaV1.2 channels in reactive astrocytes. At the age of 6 month, CaV1.2 channels were rarely detected in reactive astrocytes of transgenic mice, but an incremental number of CaV1.2 expressing reactive astrocytes was found with increasing age of animals and number of amyloid-β plaques. This study demonstrates that CaV1.2 channels are highly expressed in reactive astrocytes of 12-months of age transgenic mice, which might be a consequence of the increasing amyloid burden. Further studies should clarify which functional implications are associated with the higher availability of CaV1.2 channels in late stage Alzheimer's disease.
