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β-amyloid monomer scavenging by an anticalin protein prevents neuronal hyperactivity in mouse models of Alzheimer’s Disease
Nature Communications ( IF 14.7 ) Pub Date : 2024-07-10 , DOI: 10.1038/s41467-024-50153-y
Benedikt Zott 1, 2, 3, 4 , Lea Nästle 5 , Christine Grienberger 1, 6 , Felix Unger 1, 2, 3 , Manuel M Knauer 1 , Christian Wolf 1, 2 , Aylin Keskin-Dargin 1 , Anna Feuerbach 5 , Marc Aurel Busche 1, 7 , Arne Skerra 5 , Arthur Konnerth 1, 4
Affiliation  

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.



中文翻译:


Anticalin 蛋白清除 β-淀粉样蛋白单体可预防阿尔茨海默氏病小鼠模型中的神经元过度活跃



由突触毒性 β-淀粉样蛋白 (Aβ) 寡聚物介导的过度活跃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的过程中,我们测试了在 Aβ 斑块形成​​之前清除 Aβ 肽的效果。在海马切片中使用体内双光子钙成像和基于 SF-iGluSnFR 的谷氨酸成像,我们证明 Aβ 结合 anticalin 蛋白(Aβ-anticalin)可以抑制 APP23xPS45 小鼠模型中的早期神经元过度活跃和突触谷氨酸积累。淀粉样变性。我们的结果表明,仅针对 Aβ 单体就足以实现 Aβ-anticalin 在疾病早期阶段的多动抑制作用。生化和神经生理学分析表明,天然分泌的 Aβ 单体的 Aβ 抗运蛋白依赖性消耗会中断它们聚集成神经毒性寡聚体,从而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发挥着关键作用。

更新日期:2024-07-11
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