Development Of Cajal-Retzius Cells, Alterations Of Glutamatergic And GABAergic Neurons And Expressions Of Glutamate And GABA_A Receptors In APPswe Transgenic Mouse

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases of the central nervous system, so far its etiology and pathogenesis still remain unclear. APPswe transgenic mouse, which expresses "Swedish" mutant APP695 protein and producesβ-amyloid peptide, is a suitable animal model for the studies of the pathology and therapy of AD. With Thioflavine S staining, immunofluorescent labeling and western-blotting, the APPswe transgenic mice from postnatal day 0 to postnatal day 360 were used in the study, therefore, the development of Cajal-Retzuis (CR) cells, the alternation of glutamatergic and GABAergic neurons and the expression of NMDAR1,GluR2/3 and GABAAα1-6 receptors were investigated in the hippocampus. Our results showed:1. The general behaviors and pathology of APPswe trangenic mice:Morris watermaze (island seeking assay) was used to evaluate their cognitive ability. The spatial determination of 9 months old APPswe transgenic mice was much worse than the wild type mice at same age. On the other hand, Thioflavine S staining showed the amyloid plaques in cortex and hippocampus of transgenic mice after the age of 9 months. However, no any amyloid plaque was found in wild type mice.2. The normal development of Cajal-Retzius cells and their changes in APPswe transgenic mice:Cajal-Retzius cell (CR cell) is a kind of pioneer neurons, which are involved in neuronal migration and lamination of neocortex and archicortex as well. This study observed the development of CR cells with immunofluorescent labeling. Results showed that Reelin positive CR cells appeared in molecular layer of dentate gyrus as early as at embryonic day 16, and with age increasing the number of CR cells decreased. However, comparing with wild type, CR cells in APPswe transgenic mice had significantly decreased after P180 in the molecular layer of the dentate gyrus (P<0.05) . The reelin expression in hippocampus with western blot analysis showed similar results as immunocytochemistry, suggesting that CR cells in may play an important role in AD pathogenesis.3. Glutamatergic and GABAergic neurons in the hippocampus of Appswe transgenic mice:Glutamate andγ-aminobutyric acid (GABA) are the principal excitatory and inhibitory neurotransmitters in brain. In order to understand their functions in AD pathogenesis, the development of glutamatergic and GABAergic neurons in the hippocampus of APPswe transgenic mice were investigated. The results showed: the glutamatergic neurons were mainly the pyramidal cells in pyramidal layer, and the GABAergic neurons were mainly the interneurons in molecular layer and orien of hippocampal proper. In both wild type and transgenic mice, the numbers of glutamatergic and GABAergic neurons in CA1 and CA3 areas decreased gradually with age increasing. But the glutamatergic neurons in transgenic mice were much less than wild type mice after P90 (P<0.05). On the other hand, the number of GABAergic neurons in hippocampus had no obvious difference between the two kinds of mice, although the density of GABAergic neurons in transgenic mice on P360 had decreased 27.1% compared with wild type, but no statistically significant difference between them. Our results suggested that Glutamate probably served as an excitotoxicity for the pathogenesis of AD, and GABA may function as a protective effect in AD injury.4. Glutamate and GABA_A receptors in the hippocampus of APPswe transgenic mice:NMDAR1 and GluR2/3 are two of important ionotropic glutamate receptor, which mediated fast excitatory synaptic transmission, and involved in almost all of the brain physiological functions. On the other hand, GABAA receptor is one of ionotropic GABA receptors which is widely distributed in the central nervous system and contributed to fast inhibitory transmission. In the study, the expression of NMDAR1, GluR2/3 and GABAAα1-6R in hippocampus were investigated in wild type mice and APPswe transgenic mice as well. Results showed: NMDAR1 and GluR2/3 usually expressed on the surface of hippocampal pyramidal cells. Both NMDAR1 and GluR2/3 positive pyramidal cells decreased gradually with age increasing. The density of positive cells in transgenic mice after P360 significantly decreased, compared with wild type (P<0.05) . Interestingly, the expression of GABAAα1-6R had no obvious changes with age increasing in both wild type and transgenic mice. The density of the positive cells in transgenic mice at P360 slightly decreased comparing with wild type, but no statistically significant difference. The results were further supported with western blot analysis of NMDAR1 and GABAAal-6R expression in hippocampus. Our study suggested that glutamate receptors may play an important role in the development of Alzheimer's disease and GABAARα1-6 may be combined GABA played a protective effect in the neuronal damage of AD.In Conclusion: In this study, CR cells, glutamatergic/GABAergic neurons and glutamate/GABA receptors in hippocampus have correlation with the development of AD. The results probably provide us useful clues for to further explore the pathogenesis and therapy of AD.