Apolipoprotein E Isoforms Increase Intracellular Ca2+ Differentially Through a ω-Agatoxin IVa-Sensitive Ca2+-Channel

Apolipoprotein E (apoE) is the major apolipoprotein in the brain and is known for its important role in plasticity and neurodegeneration. We show that apoE dose-dependently increases intracellular free Ca²⁺ in rat hippocampal astrocytes and neurons. This effect varies with isoforms in the order E4>E3>E2. It is insensitive to blockade of action potentials by tetrodotoxin or inhibition of binding of apoE by heparinase, by the LRP ligand lactoferrin and by low density lipoprotein. ApoE evoked Ca²⁺-increases are blocked in zero [Ca]o and by the Ca-channel antagonists nickel and ω-Agatoxin-IVa but not by nifedipine and ω-Conotoxin-GVIa, demonstrating an isoform-specific activation of P/Q type Ca²⁺-channels. This novel mechanism is discussed with respect to Alzheimer's disease, that is linked for most cases to the apoE ε-allelic variation (ε4 > ε3 > ε2).