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Hippocampal stem cells promotes synaptic resistance to the dysfunctional impact of amyloid beta oligomers via secreted exosomes.
Molecular Neurodegeneration ( IF 14.9 ) Pub Date : 2019-06-14 , DOI: 10.1186/s13024-019-0322-8
Maria-Adelaide Micci 1 , Balaji Krishnan 2 , Elizabeth Bishop 1 , Wen-Ru Zhang 2 , Jutatip Guptarak 1 , Auston Grant 1 , Olga Zolochevska 2 , Batbayar Tumurbaatar 2 , Whitney Franklin 2 , Claudia Marino 2 , Steven G Widen 3 , Arjun Luthra 4 , Steven G Kernie 5 , Giulio Taglialatela 2
Affiliation  

BACKGROUND Adult hippocampal neurogenesis plays an important role in synaptic plasticity and cogntive function. We reported that higher numbers of neural stem cells (NSC) in the hippocampus of cognitively-intact individuals with high Alzheimer's disease (AD) pathology (plaques and tangles) is associated with decreased synaptic amyloid beta oligomers (Aβο), an event linked to onset of dementia in AD. While these findings suggest a link between NSC and synaptic resistance to Aβο, the involved mechanism remains to be determined. With this goal in mind, here we investigated the ability of exosomes secreted from hippocampal NSC to promote synaptic resilience to Aβo. METHODS Exosomes isolated from media of hippocampus NSC (NSC-exo) or mature hippocampal neuronal (MN-exo) cultures were delivered intracerebroventricularly (ICV) to mice before assessment of Aβο-induced suppression of hippocampal long-term potentiation (LTP) and memory deficits. Aβο binding to synapses was assessed in cultured hippocampal neurons and on synaptosomes isolated from hippocampal slices from wild type mice and from an inducible mouse model of NSC ablation (Nestin-δ-HSV-TK mice) treated with exosomes. Expression of CaMKII and of AMPA and NMDA glutamate receptor subunits in synaptosomes was measured by western blot. Small RNA Deep sequencing was performed to identify microRNAs enriched in NSC-exo as compared to MN-exo. Mimics of select miRNAs were injected ICV. RESULTS NSC-exo, but not MN-exo, abolished Aβo-induced suppression of LTP and subsequent memory deficits. Furthermore, in hippocampal slices and cultured neurons, NSC-exo significantly decreased Aβo binding to the synapse. Similarly, transgenic ablation of endogenous NSC increased synaptic Aβo binding, which was reversed by exogenous NSC-exo. Phosphorylation of synaptic CaMKII was increased by NSC-exo, while AMPA and NMDA receptors were not affected. Lastly, we identified a set of miRNAs enriched in NSC-exo that, when injected ICV, protected the synapses from Aβo-binding and Aβo-induced LTP inhibition. CONCLUSIONS These results identify a novel mechanism linking NSC-exo and synaptic susceptibility to Aβo that may underscore cognitive resilience of certain individuals with increased neurogenesis in spite of AD neuropathology and unmask a novel target for the development of a new treatment concept for AD centered on promoting synaptic resilience to toxic amyloid proteins.

中文翻译:


海马干细胞通过分泌的外泌体促进突触抵抗β淀粉样蛋白寡聚物的功能障碍影响。



背景成人海马神经发生在突触可塑性和认知功能中起着重要作用。我们报道,患有阿尔茨海默病(AD)病理(斑块和缠结)的认知完整个体的海马中神经干细胞(NSC)数量较多与突触淀粉样蛋白β寡聚体(Aβο)减少有关,这是与发病相关的事件AD 中的痴呆症。虽然这些发现表明 NSC 与 Aβο 突触抗性之间存在联系,但所涉及的机制仍有待确定。考虑到这一目标,我们在这里研究了海马 NSC 分泌的外泌体促进 Aβo 突触弹性的能力。方法 从海马 NSC (NSC-exo) 或成熟海马神经元 (MN-exo) 培养物中分离出的外泌体经脑室内 (ICV) 递送至小鼠,然后评估 Aβο 诱导的海马长时程增强 (LTP) 抑制和记忆缺陷。在培养的海马神经元以及从野生型小鼠和用外泌体处理的 NSC 消融诱导小鼠模型(Nestin-δ-HSV-TK 小鼠)的海马切片中分离的突触体中评估了 Aβο 与突触的结合。通过蛋白质印迹测量突触体中 CaMKII 以及 AMPA 和 NMDA 谷氨酸受体亚基的表达。进行小 RNA 深度测序,以鉴定与 MN-exo 相比,NSC-exo 中富集的 microRNA。通过 ICV 注射选定 miRNA 的模拟物。结果 NSC-exo(而非 MN-exo)消除了 Aβo 诱导的 LTP 抑制和随后的记忆缺陷。此外,在海马切片和培养的神经元中,NSC-exo 显着降低了 Aβo 与突触的结合。类似地,内源性 NSC 的转基因消融增加了突触 Aβo 结合,而外源性 NSC-exo 则逆转了这种情况。 NSC-exo 增加了突触 CaMKII 的磷酸化,而 AMPA 和 NMDA 受体不受影响。最后,我们鉴定了一组富含 NSC-exo 的 miRNA,当注射 ICV 时,它们可以保护突触免受 Aβo 结合和 Aβo 诱导的 LTP 抑制。结论 这些结果确定了一种将 NSC-exo 和突触对 Aβo 的易感性联系起来的新机制,该机制可能会强调某些神经发生增加的个体的认知弹性,尽管存在 AD 神经病理学,并揭示了开发以促进 AD 为中心的新治疗概念的新目标。突触对有毒淀粉样蛋白的恢复能力。
更新日期:2020-04-22
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