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

靶向Aβ寡聚体（AβOs）的免疫治疗中钙（Ca^2+）稳态的分子机制仍有待确定。我们发现，AβOs可引起活细胞胞浆中钙（Ca^2+）超载。抗A βO抗体72 D9几乎阻断了非Tg或3x Tg-AD小鼠皮质神经元胞浆Ca^2+超载，表明胞浆Ca^2+超载来源于细胞外Ca^2+。N-甲基-D-天冬氨酸（NMDA）拮抗剂和L-型电压依赖性钙通道（L-VDDC）阻断剂都不能减弱它们，这表明膜完整性的损害是由于Aβ O依赖性作用，如Ca^2+孔的形成。因此，在神经元中，单克隆72 D9通过特异性控制细胞外AβOs，作为病理性Ca^2+稳态的调节剂。

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.