Molecular mechanisms underlying Alzheimer's neurodegeneration:implication for A βoligomer Ca^2+ channels

针对Aβ寡聚体(AβOs)的免疫治疗中钙(Ca^2)动态平衡的分子机制尚不清楚。我们发现A-β-OS导致活细胞胞浆内钙超载。抗AβO抗体72D9几乎阻断了非TG或3x TG-AD小鼠皮质神经元胞浆Ca^2超载，表明胞内Ca^2超载来源于细胞外Ca^2。N-甲基-D-天冬氨酸受体激动剂和L类电压依赖性钙通道阻滞剂均不能减弱膜的完整性，提示膜完整性的损害是由于β的氧依赖作用，如钙离子孔道的形成。因此，在神经元中，单抗72D9通过细胞外AβOs的特异性控制，发挥病理性钙稳态的调节剂作用。

The molecular mechanism of calcium (Ca^2+) homeostasis underlying immunotherapy targeting Aβ oligomers (AβOs) remains to be determined. We found that AβOs caused calcium (Ca^2+) overload in the cytosol of viable cells. The anti-AβO antibody 72D9afforded a near blockade of cytosolic Ca^2+ overload in cortical neurons obtained from either non-Tg or 3x Tg-AD mice, indicating that cytosolic Ca^2+ overload originates from extracellular Ca^2+. Neither N-methyl-D-aspartic acid (NMDA) anatagonists nor L-type voltage-dependent Ca^2+ channel (L-VDDC) blockers also attenuated them, suggesting that the impairment of membrane integrity was owing to AβO-depending action such as a pore formation for Ca^2+. Thus, in neurons, monoclonal 72D9 acts as a modulator of pathological Ca^2+ -homeostasis via specific control of extracellular AβOs.