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Selected microRNAs Increase Synaptic Resilience to the Damaging Binding of the Alzheimer's Disease Amyloid Beta Oligomers.
Molecular Neurobiology ( IF 5.1 ) Pub Date : 2020-01-29 , DOI: 10.1007/s12035-020-01868-8
Olga Zolochevska 1 , Giulio Taglialatela 1
Affiliation  

Alzheimer's disease (AD) is marked by synaptic loss (at early stages) and neuronal death (at late stages). Amyloid beta (Aβ) and tau oligomers can target and disrupt synapses thus driving cognitive decay. Non-demented individuals with Alzheimer's neuropathology (NDAN) are capable of withstanding Aβ and tau toxicity, thus remaining cognitively intact despite presence of AD neuropathology. Understanding the involved mechanism(s) would lead to development of novel effective therapeutic strategies aimed at promoting synaptic resilience to amyloid toxicity. NDAN have a unique hippocampal post-synaptic proteome when compared with AD and control individuals. Potential upstream modulators of such unique proteomic profile are miRNA-485, miRNA-4723 and miRNA-149, which we found differentially expressed in AD and NDAN vs. control. We thus hypothesized that these miRNAs play an important role in promoting either synaptic resistance or sensitization to Aβ oligomer binding. Using an in vivo mouse model, we found that administration of these miRNAs affected key synaptic genes and significantly decreased Aβ binding to the synapses. Our findings suggest that miRNA regulation and homeostasis are crucial for Aβ interaction with synaptic terminals and support that a unique miRNA regulation could be driving synaptic resistance to Aβ toxicity in NDAN, thus contributing to their preserved cognitive abilities.

中文翻译:

选定的 microRNA 增加了对阿尔茨海默病淀粉样蛋白 β 寡聚体的破坏性结合的突触恢复力。

阿尔茨海默病 (AD) 的特点是突触丧失(早期)和神经元死亡(晚期)。β 淀粉样蛋白 (Aβ) 和 tau 寡聚体可以靶向和破坏突触,从而导致认知衰退。患有阿尔茨海默病神经病理学 (NDAN) 的非痴呆个体能够承受 Aβ 和 tau 毒性,因此尽管存在 AD 神经病理学,但仍保持认知完整。了解所涉及的机制将导致开发新的有效治疗策略,旨在促进突触对淀粉样蛋白毒性的恢复。与 AD 和对照个体相比,NDAN 具有独特的海马突触后蛋白质组。这种独特蛋白质组谱的潜在上游调节剂是 miRNA-485、miRNA-4723 和 miRNA-149,我们发现它们在 AD 和 NDAN 与对照中差异表达。因此,我们假设这些 miRNA 在促进突触抗性或对 Aβ 寡聚体结合敏感方面发挥重要作用。使用体内小鼠模型,我们发现施用这些 miRNA 会影响关键突触基因并显着降低 Aβ 与突触的结合。我们的研究结果表明,miRNA 调节和稳态对于 Aβ 与突触末端的相互作用至关重要,并支持独特的 miRNA 调节可能驱动 NDAN 中对 Aβ 毒性的突触抗性,从而有助于它们保存的认知能力。
更新日期:2020-04-22
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