Dendritic and axonal mechanisms of Ca2+ elevation impair BDNF transport in Aβ oligomer-treated hippocampal neurons.
Dendritic and axonal mechanisms of Ca2+ elevation impair BDNF transport in Aβ oligomer-treated hippocampal neurons.
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DOI：
10.1091/mbc.e14-12-1612
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发表时间：
2015-03-15
影响因子：
3.3
通讯作者：
Silverman MA
中科院分区：
文献类型：
--
作者：
Gan KJ;Silverman MA
阿尔茨海默病中细胞内Ca2+失调和转运中断先于细胞死亡确定了Aβ O诱导的Ca2+升高的机制，其调节BDNF转运缺陷的发生、严重程度和时空进展。这些结果挑战了关于AβO毒性机制和亚细胞作用位点的教条观点。快速轴突运输（FAT）的破坏和细胞内Ca 2+失调是阿尔茨海默病（AD）的早期病理事件。淀粉样β寡聚体（AβOs）是AD的致病因子，它通过非兴奋毒性激活钙调神经磷酸酶（CaN）而损害BDNF的转运，而不依赖于tau蛋白。调节树突和轴突AβO结合位点BDNF转运缺陷的发生、严重程度和时空进展的钙依赖性机制尚不清楚。在这里，我们表明，BDNF的运输缺陷在树突和轴突的诱导同时，但表现出不同的下降率。FAT损伤的时空进展首先在树突中，随后在轴突中与Ca2+升高和CaN激活相关。尽管AD中描述了许多轴突病理，但研究主要集中在AβOs的树突效应上，尽管AD模型和患者中有令人信服的突触前AβOs报告。事实上，我们观察到，树突状细胞CaN激活收敛于通过轴突电压门控Ca2+通道的Ca2+内流损害FAT。最后，脂肪缺陷是防止丹曲林，一种临床化合物，减少Ca2+释放的ER。这项工作确立了早期AD中Ca2+失调在BDNF转运中断和tau非依赖性Aβ毒性中的新作用。
Intracellular Ca2+ dysregulation and transport disruption precede cell death in Alzheimer's disease. Mechanisms of AβO-induced Ca2+ elevation are identified that regulate the onset, severity, and spatiotemporal progression of BDNF transport defects. The results challenge dogmatic views on mechanisms of AβO toxicity and subcellular sites of action. Disruption of fast axonal transport (FAT) and intracellular Ca2+ dysregulation are early pathological events in Alzheimer's disease (AD). Amyloid-β oligomers (AβOs), a causative agent of AD, impair transport of BDNF independent of tau by nonexcitotoxic activation of calcineurin (CaN). Ca2+-dependent mechanisms that regulate the onset, severity, and spatiotemporal progression of BDNF transport defects from dendritic and axonal AβO binding sites are unknown. Here we show that BDNF transport defects in dendrites and axons are induced simultaneously but exhibit different rates of decline. The spatiotemporal progression of FAT impairment correlates with Ca2+ elevation and CaN activation first in dendrites and subsequently in axons. Although many axonal pathologies have been described in AD, studies have primarily focused only on the dendritic effects of AβOs despite compelling reports of presynaptic AβOs in AD models and patients. Indeed, we observe that dendritic CaN activation converges on Ca2+ influx through axonal voltage-gated Ca2+ channels to impair FAT. Finally, FAT defects are prevented by dantrolene, a clinical compound that reduces Ca2+ release from the ER. This work establishes a novel role for Ca2+ dysregulation in BDNF transport disruption and tau-independent Aβ toxicity in early AD.