中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2024, Vol. 19 ›› Issue (9): 2068-2074.doi: 10.4103/1673-5374.390963

• 原著:退行性病与再生 • 上一篇    下一篇

海马兴奋性突触结构和分子变化复原力有助于 Tg2576 小鼠认知功能的恢复

  

  • 出版日期:2024-09-15 发布日期:2024-01-26

Resilience to structural and molecular changes in excitatory synapses in the hippocampus contributes to cognitive function recovery in Tg2576 mice

Carolina Aguado1, #, Sara Badesso2, #, José Martínez-Hernández1, #, †, Alejandro Martín-Belmonte3, 4, Rocío Alfaro-Ruiz1, #br# Miriam Fernández1, Ana Esther Moreno-Martínez1, Mar Cuadrado-Tejedor2, 5, Ana García-Osta2, *, Rafael Luján1, *   

  1. 1Synaptic Structure Laboratory, Instituto de Investigación en Discapacidades Neurológicas (IDINE), Department of Medical Sciences, Facultad de Medicina, Universidad de Castilla-La Mancha, Campus Biosanitario, Albacete, Spain; 2Gene Therapy for Neurological Disease Program, Center for Applied Medical Research (CIMA), University of Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; 3Pharmacology Unit, Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, Barcelona, Spain; 4Neuropharmacology and Pain Group, Neuroscience Program, Institut d’Investigació Biomèdica de Bellvitge, IDIBELL, L’Hospitalet de Llobregat, Spain; 5Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain
    †Current address: Université Grenoble Alpes, Grenoble Institut des Neurosciences, Grenoble, France
  • Online:2024-09-15 Published:2024-01-26
  • Contact: Ana García-Osta, PhD, agosta@unav.es; Rafael Luján, PhD, Rafael.Lujan@uclm.es.
  • Supported by:
    This work was supported by grant PID2021-125875OB-I00 funded by MCIN/AEI/ 10.13039/501100011033 and by “ERDF A way of making Europe” (to RL). This work was also supported by a grant from Junta de Comunidades de Castilla-La Mancha (SBPLY/21/180501/000064) and Universidad de Castilla-La Mancha (2023-GRIN-34187) (to RL). Grant PID2019-104921RB-I00/MCI/AEI/10.13039/501100011033 (to AGO). We are also grateful to the Foundation for Applied Medical Research, the University of Navarra (Pamplona, Spain) for financial support and the Asociación de Amigos of the University of Navarra for the grant (to SB), and Margarita Salas fellowship from Ministerio de Universidades and Universidad de Castilla-La Mancha (to AMB).

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摘要：

淀粉样β蛋白（Aβ）斑块和神经纤维缠结是阿尔茨海默病（AD）的主要病理特征。一些患有阿尔茨海默病的老年人仍能保持认知功能，揭示阿尔茨海默病的认知恢复能力的因素为确定新的治疗靶点提供了广阔的前景。实验假设兴奋性突触在结构和分子水平上的变化对阿尔茨海默病认知功能的恢复有贡献；由此，利用Morris水迷宫测试选择了具有恢复能力（无症状）和认知功能受损的老年 Tg2576 小鼠。虽然酶联免疫吸附试验（ELISA）显示两个实验组的Aβ42水平相似，但使用Western印迹显示突触前上清液部分的tau病理学存在差异。为了深入研究16-18个月大的Tg2576小鼠海马内的突触密度，采用了体视学和电子显微镜方法进行观察。研究结果显示，与年龄匹配的具有恢复能力的Tg2576小鼠和非转基因对照组（WT）相比，Tg2576受损小鼠CA1区放射状层的兴奋性突触密度有所下降。有趣的是，通过定量免疫电镜观察受损和恢复能力强的 Tg2576 转基因 AD 小鼠的海马，发现了谷氨酸受体亚细胞定位的差异。具体来说，与年龄匹配的具有恢复能力的Tg2576小鼠和非转基因对照组相比，受损的Tg2576小鼠CA1锥体细胞棘突和树突轴中的GluA1、GluA2/3和mGlu5的密度显著降低。值得注意的是，与受损的 Tg2576 小鼠和 WT 小鼠相比，有恢复能力的 Tg2576 小鼠棘突中的 GluA2/3 密度明显增加，但树突轴中的密度却没有增加。这些亚细胞研究结果有力地支持了海马树突棘可塑性和突触机制在Tg2576小鼠认知恢复机制中发挥关键作用的假设。

https://orcid.org/0000-0001-6326-9064 (Ana García Osta); https://orcid.org/0000-0003-2001-9545 (Rafael Luján)

Abstract: Plaques of amyloid-β (Aβ) and neurofibrillary tangles are the main pathological characteristics of Alzheimer’s disease (AD). However, some older adult people with AD pathological hallmarks can retain cognitive function. Unraveling the factors that lead to this cognitive resilience to AD offers promising prospects for identifying new therapeutic targets. Our hypothesis focuses on the contribution of resilience to changes in excitatory synapses at the structural and molecular levels, which may underlie healthy cognitive performance in aged AD animals. Utilizing the Morris Water Maze test, we selected resilient (asymptomatic) and cognitively impaired aged Tg2576 mice. While the enzyme-linked immunosorbent assay showed similar levels of Aβ42 in both experimental groups, western blot analysis revealed differences in tau pathology in the pre-synaptic supernatant fraction. To further investigate the density of synapses in the hippocampus of 16–18 month-old Tg2576 mice, we employed stereological and electron microscopic methods. Our findings indicated a decrease in the density of excitatory synapses in the stratum radiatum of the hippocampal CA1 in cognitively impaired Tg2576 mice compared with age-matched resilient Tg2576 and non-transgenic controls. Intriguingly, through quantitative immunoelectron microscopy in the hippocampus of impaired and resilient Tg2576 transgenic AD mice, we uncovered differences in the subcellular localization of glutamate receptors. Specifically, the density of GluA1, GluA2/3, and mGlu5 in spines and dendritic shafts of CA1 pyramidal cells in impaired Tg2576 mice was significantly reduced compared with age-matched resilient Tg2576 and non-transgenic controls. Notably, the density of GluA2/3 in resilient Tg2576 mice was significantly increased in spines but not in dendritic shafts compared with impaired Tg2576 and non-transgenic mice. These subcellular findings strongly support the hypothesis that dendritic spine plasticity and synaptic machinery in the hippocampus play crucial roles in the mechanisms of cognitive resilience in Tg2576 mice.

Key words: aging, Alzheimer′s disease, cognitive, hippocampus, immunoelectron microscopy, resilience, synapse