PDF(Pubmed)
Abstract：
Hyperactivity mediated by synaptotoxic β-amyloid (Aβ) oligomers is one of the earliest forms of neuronal dysfunction in Alzheimer\'s disease. In the search for a preventive treatment strategy, we tested the effect of scavenging Aβ peptides before Aβ plaque formation. Using in vivo two-photon calcium imaging and SF-iGluSnFR-based glutamate imaging in hippocampal slices, we demonstrate that an Aβ binding anticalin protein (Aβ-anticalin) can suppress early neuronal hyperactivity and synaptic glutamate accumulation in the APP23xPS45 mouse model of β-amyloidosis. Our results suggest that the sole targeting of Aβ monomers is sufficient for the hyperactivity-suppressing effect of the Aβ-anticalin at early disease stages. Biochemical and neurophysiological analyses indicate that the Aβ-anticalin-dependent depletion of naturally secreted Aβ monomers interrupts their aggregation to neurotoxic oligomers and, thereby, reverses early neuronal and synaptic dysfunctions. Thus, our results suggest that Aβ monomer scavenging plays a key role in the repair of neuronal function at early stages of AD.
摘要：
突触毒性β-淀粉样蛋白（Aβ）寡聚体介导的过度活动是阿尔茨海默病神经元功能障碍的最早形式之一。在寻找预防性治疗策略时，我们测试了在Aβ斑块形成之前清除Aβ肽的效果。使用体内双光子钙成像和基于SF-iGluSnFR的海马切片谷氨酸成像，我们证明，在APP23xPS45β淀粉样变性小鼠模型中，Aβ结合抗素蛋白（Aβ-抗素）可以抑制早期神经元过度活动和突触谷氨酸积累。我们的结果表明，Aβ单体的唯一靶向作用足以在疾病早期抑制Aβ-抗林剂的过度活跃作用。生化和神经生理学分析表明，自然分泌的Aβ单体的Aβ-抗血清依赖性消耗中断了它们向神经毒性寡聚体的聚集，因此，逆转早期神经元和突触功能障碍。因此，我们的结果表明，Aβ单体清除在AD早期神经元功能的修复中起关键作用。
