Neural Regeneration Research ›› 2024, Vol. 19 ›› Issue (9): 2068-2074.doi: 10.4103/1673-5374.390963

Previous Articles     Next Articles

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).

PDF

45

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