Calabrese Barbara, Shaked Gideon M, Tabarean Iustin V, Braga Julia, Koo Edward H, Halpain Shelley
Department of Cell Biology and Institute for Childhood and Neglected Diseases, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037, USA.
Mol Cell Neurosci. 2007 Jun;35(2):183-93. doi: 10.1016/j.mcn.2007.02.006. Epub 2007 Feb 12.
In Alzheimer's disease increasing evidence attributes synaptic and cognitive deficits to soluble oligomers of amyloid beta protein (Abeta), even prior to the accumulation of amyloid plaques, neurofibrillary tangles, and neuronal cell death. Here we show that within 1-2 h picomolar concentrations of cell-derived, soluble Abeta induce specific alterations in pre- and postsynaptic morphology and connectivity in cultured hippocampal neurons. Clusters of presynaptic vesicle markers decreased in size and number at glutamatergic but not GABAergic terminals. Dendritic spines also decreased in number and became dysmorphic, as spine heads collapsed and/or extended long protrusions. Simultaneous time-lapse imaging of axon-dendrite pairs revealed that shrinking spines sometimes became disconnected from their presynaptic varicosity. Concomitantly, miniature synaptic potentials decreased in amplitude and frequency. Spine changes were prevented by blockers of nAChRs and NMDARs. Washout of Abeta within the first day reversed these spine changes. Further, spine changes reversed spontaneously by 2 days, because neurons acutely developed resistance to continuous Abeta exposure. Thus, rapid Abeta-induced synapse destabilization may underlie transient behavioral impairments in animal models, and early cognitive deficits in Alzheimer's patients.
在阿尔茨海默病中，越来越多的证据将突触和认知缺陷归因于β淀粉样蛋白（Aβ）的可溶性寡聚体，甚至在淀粉样斑块、神经原纤维缠结和神经元细胞死亡积累之前。在这里，我们表明，在1-2小时内，皮摩尔浓度的细胞衍生可溶性Aβ会在培养的海马神经元中引起突触前和突触后形态及连接性的特定改变。在谷氨酸能而非GABA能终末，突触前囊泡标记物簇的大小和数量减少。树突棘数量也减少并变得畸形，因为棘头塌陷和/或伸出长突起。轴突-树突对的同步延时成像显示，萎缩的棘有时会与其突触前膨体断开连接。同时，微小突触电位的幅度和频率降低。烟碱型乙酰胆碱受体（nAChRs）和N-甲基-D-天冬氨酸受体（NMDARs）的阻滞剂可防止棘的变化。在第一天内洗脱Aβ可逆转这些棘的变化。此外，棘的变化在2天内自发逆转，因为神经元会迅速对持续的Aβ暴露产生抗性。因此，快速的Aβ诱导的突触不稳定可能是动物模型中短暂行为损伤以及阿尔茨海默病患者早期认知缺陷的基础。
