Resilience to changes in hippocampal excitatory synapses contribute to cognitively healthy Tg2576 mice

Some individuals with Alzheimer’s disease (AD) pathology exhibit cognitive resilience, offering promising prospects for identifying new therapeutic targets.Aims: Our hypothesis centers around 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.Methods: We used Morris Water Maze tests, ELISA, western blots, stereological methods and immunoelectron microscopy.Results: Utilizing the Morris Water Maze test, we selected resilient (asymptomatic) and cognitively impaired aged-Tg2576 mice. While ELISA showed similar levels of Aβ42 between the two groups, western blots revealed differences in tau pathology in the pre-synaptic supernatant fraction. Using stereological methods at the electron microscopic level, our findings indicated a decrease in excitatory synapse density in the stratum radiatum of the CA1 field in impaired Tg2576 mice compared to age-matched resilient Tg2576 and non-transgenic controls (WT). In addition, 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 to age-matched resilient Tg2576 and non-transgenic controls. Notably, the density of GluA2/3 in resilient Tg2576 was significantly increased in spines but not in dendritic shafts when compared to impaired Tg2576 and WT mice.Conclusions: These subcellular findings strongly support the hypothesis that spine plasticity and synaptic machinery play crucial roles in the mechanisms of cognitive resilience in Tg2576 mice.Grant PID2021-125875OB-I00 funded by MCIN/AEI/ 10.13039/501100011033 and “ERDF A way of making Europe”, and Junta de Comunidades de Castilla-La Mancha (SBPLY/21/180501/000064)