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

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.

Cellular Prion Protein and Sexual Dimorphic Areas in Rodents. Correlates with Alzheimer Disease

The cellular prion protein (PrPC) expression was analyzed by western-blot in the rat, in two different dimorphic brain areas such as the anterior hypothalamic and the preoptic areas. In both cases, the PrPC expression was increased in males, implying a sexual dimorphism for the PrPC protein. The study was also made in other two brain areas, frontal cortex and hyppocampus (a clearly dimorphic area);in this case, mice of different ages of both sexes were used. In both brain areas analyzed, although the PrPC expression was increased with age until the adult age (38 weeks), it was decreased in aged animals (56 weeks) in both sexes. The PrPC expression in mouse hippocampus was predominant in males in comparison to females. Moreover, the non-glycosylated band was increased with age and this increase was parallel with the increase observed for the glycolsylated band. The non-glycosylated band increases more in aged females. Altogether, these data suggest that PrP in rodents, in the brain areas analyzed, has a dimorphism role. As we discuss in the present study and in relation to previous studies of our group these data could be extrapolated to humans (specially in Alzhemer disease cases).