A Role for Synaptic Zinc in Activity-Dependent Aβ Oligomer Formation and Accumulation at Excitatory Synapses
A Role for Synaptic Zinc in Activity-Dependent Aβ Oligomer Formation and Accumulation at Excitatory Synapses
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DOI：
10.1523/jneurosci.5980-08.2009
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发表时间：
2009-04-01
影响因子：
5.3
通讯作者：
Busciglio, Jorge
中科院分区：
文献类型：
--
作者：
Deshpande, Atul;Kawai, Hideki;Busciglio, Jorge
可溶性淀粉样蛋白β寡聚体（A β O）干扰突触功能并以高亲和力与突触结合，但A β O突触靶向的潜在机制尚不清楚。在这里，我们表明，合成或本地阿尔茨海默氏病（AD）-脑寡聚体在突触的积累是由突触活动调节。电刺激或化学刺激增加了A β O突触定位，并增强了突触末端的寡聚体形成，而TTX抑制则阻断了A β O突触定位，并降低了A β O突触负荷。锌结合的8-OH-喹啉氯碘羟喹显著降低A β O突触靶向，这在突触囊泡锌转运蛋白ZnT 3缺陷的动物的脑切片中也降低，表明神经传递期间释放的囊泡锌对于A β O突触靶向至关重要。寡聚体没有内化在回收囊泡，但仍然在细胞表面，在那里他们与NR 2B NMDA受体亚基共定位。此外，NMDA拮抗剂阻断A β O突触靶向，暗示兴奋性受体活性在突触处的寡聚体形成和积累中。在AD脑中，不同大小的寡聚体与海马和皮质中的突触标记物共定位，其中寡聚体突触积累与突触损失相关。
Soluble amyloid beta oligomers (A beta Os) interfere with synaptic function and bind with high affinity to synapses, but the mechanism underlying A beta O synaptic targeting is not known. Here, we show that the accumulation of synthetic or native Alzheimer's disease (AD)-brain oligomers at synapses is regulated by synaptic activity. Electrical or chemical stimulation increased A beta O synaptic localization and enhanced oligomer formation at synaptic terminals, whereas inhibition with TTX blocked A beta O synaptic localization and reduced A beta O synaptic load. The zinc-binding 8-OH-quinoline clioquinol markedly reduced A beta O synaptic targeting, which was also reduced in brain sections of animals deficient in the synaptic vesicle zinc transporter ZnT3, indicating that vesicular zinc released during neurotransmission is critical for A beta Osynaptic targeting. Oligomers were not internalized in recycled vesicles but remained at the cell surface, where they colocalized with NR2B NMDA receptor subunits. Furthermore, NMDA antagonists blocked A beta O synaptic targeting, implicating excitatory receptor activity in oligomer formation and accumulation at synapses. In AD brains, oligomers of different size colocalized with synaptic markers in hippocampus and cortex, where oligomer synaptic accumulation correlated with synaptic loss.