Ca V 1.2 Calcium Channel Expression in Reactive Astrocytes is associated with the Formation of Amyloid-β Plaques in an Alzheimer's Disease Mouse Model

Increased activity of L-type Ca²⁺ channels has been implicated in the pathogenesis of dementia and Alzheimer's disease (AD). Previously we detected Ca_V1.2 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 Ca_V1.2 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 Ca_V1.2 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 Ca_V1.2 α₁-subunit labeling was found in 2 and 4 month-old wt and tg mice prior to plaque formation. The Ca_V1.2 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 Ca_V1.2 α₁-subunit immunoreactivity. Together these results indicate that the expression of Ca_V1.2 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.