Affiliations: [a] Department of Psychiatry and Psychotherapy, University Clinic of General and Social Psychiatry, Innsbruck Medical University, Innsbruck, Austria | [b] Division of Physiology, Innsbruck Medical University, Innsbruck, Austria | [c] Department of Neurology, Innsbruck Medical University, Innsbruck, Austria | [d] JSW-CNS ResearchQPS-Austria GmbH, Forschungslabor GmbH, Grambach, Austria | [e] Department of Psychiatry and Psychotherapy A, General Hospital LKH Hall, Milserstrasse, Austria
Correspondence:
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Correspondence to: Dr. Christian Humpel, Department of Psychiatry and Psychotherapy, Anichstr. 35, A-6020 Innsbruck, Austria. Tel.: +43 512 504 23712; Fax: +43 512 504 23713; E-mail: [email protected].
Abstract: Increased activity of L-type Ca2+ channels has been implicated in the pathogenesis of dementia and Alzheimer's disease (AD). Previously we detected CaV1.2 α1-subunit-positive expression in reactive astrocytes surrounding the plaques of 12 month-old transgenic mice overexpressing hAβPP751 with the London (V717I) and Swedish (K670M/N671L) mutations. Here we examined whether increased CaV1.2 α1-subunit expression precedes plaque formation or is specifically associated with the increased amyloid-β (Aβ) load in the plaques. Quantitative RT-PCR expression profiling of all high voltage-gated Ca2+ channel subunits (α1, β, and α2δ) revealed no difference in the hippocampi of 2, 4, and 11 month-old wild type (wt) and transgenic (tg) mice. Immunohistochemistry demonstrated that expression of CaV1.2 α1-subunit, but not of the auxiliary β4 Ca2+ channel subunit, specifically associated with Aβ-positive plaques in brains of 11 month tg mice. No difference in CaV1.2 α1-subunit labeling was found in 2 and 4 month-old wt and tg mice prior to plaque formation. The CaV1.2 α1-subunit-positive cells in 11 month-old tg mice also labeled with GFAP, but not with the microglia marker Iba1. In contrast, GFAP-positive cells induced by injection of quinolinic acid did not reveal any CaV1.2 α1-subunit immunoreactivity. Together these results indicate that the expression of CaV1.2 α1-subunits in reactive astrocytes in the tg AD mouse model is related to the increased amyloid-β load in the plaques rather than caused by effects on gene regulation or mechanisms preceding the manifestation of AD as seen by plaque formation.
