Effect Of Liver X Receptor Activation On Transformation Of Radial Glial Cells In The Hippocampus Of Wild Type And Alzheimer’s Disease Mouse And Its Mechanism

Alzheimer`S disease`s (AD) is a kind of neurodenerative disease characterized by thegradually memory loss, cognition and language impairement. The hallmark of AD is thethe deposition of β-amyloid (Aβ) peptides, neuofibrillary tangle and finally neuronal lossin the cerebral cortex and hippocampus. Neurogenesis has been described in the adulthippocampus in birds, reptiles, rodents, primates and humans. That means, there are stillnew neurons are generated in the denate gyrus(DG) of the adult hippocampus, which playprivtal role in the learning and memory. Our previous reports suggest that hippocampalneurogenesis was significantly decreased in the APP/PS1double transgenic mice model.In the adult hippocampus, the neural stem cells(NSCs) are restricted to the thinsubgranular zone(SGZ)of the hippocampus, the fate of NSCs are determined by theirniche, which is defined as a microenvironment constructed by the astrocytes, granule cellsand the factors secreted by them. The astrocytes in the adult hippocampus wascharacterized by the long process, which keeps the shape of radial glia cells (RGCs) duringthe development of the hippocampus. It was reported that this typical morphology of gliacells in the hippocampus is important, it works as the scaffold for the migration of the newborn neurons in the DG-SGZ. On the other hand, the factor Krüppel like-factor9(Klf-9)secreted by the astrocytes in the hippocampus was reported to be responsible for thematuration of the new born neuron in the DG-SGZ. It was widely accepted that themicroenvirement of the hippocampus was disturbed in the AD, modulation and controllingthe niche of the hippocampus of AD may provide a new strategy of the treatment of AD.Liver x receptors (LXR) belongs to a superfamily of nuclear receptors, it also works astranscriptors. There are two subtypes of LXR, that is LXRα and LXRβ. LXRα mainlydistributed in the liver and others organs that involved in the metablism of lipid, whileLXRβ was widely distributed in all the tissues, it was highly expressed in the centralnervous system(CNS) and participated in the metabolism of cholesterol of the brain. The target genes of LXR includeATP binding cassette transporters A1(ABCA1), ATP bindingcassette transporters G1(ABCG1) and apolipoprotein E(apoE). By modulating the functionof these genes, LXR controls the transportation of cholesterol. It demonstrated that LXRwas involved in the producing of Aβ and can relieve the memory impairment of ADmice model. It was reported that knockout of LXR α or β in APP/PS1double transgenicmouse resulted in significantly increase of Aβ deposition in the brian, when treated withthe LXR agonist TO901317, the learning and memory behavior of AD mice was obviouslyimproved. Our previous study demonstrated that LXR was involved in the transformationof radial glial cells(RGCs) to astrocytes during the development of cerebral cortex. thelong processes of RGCs were truncated and differentiated into astrocytes in advance inLXR-β knockout mice, which leads to the failure of new born neurons migration to thetarget area. During the hippocampal neurogenesis, the astrocytes in the DG-SGZ keep themorphology of radial glia cells and works as the scalfold of the migration of new bornneurons. It has not been clarified whether LXR was invovled in the transformation ofRGCs to astrocytes and modulated the niche of neural stem cells in the DG-SGZ, especiallyduring the development of AD..In present experiment, treated with LXR agonist TO901317, using immunohistochemistryand RT-PCR, we explored the effect of TO901317on the transformation of RGCs toastrocytes in the DG-SGZ and its mechanisms. By compared with the age matched wt mice,we also explored the effect of TO901317on the transformation of RGCs to astrocytes in theDG-SGZ and its possilble mechanism.Results:1．Effects of TO901317on the expression of LXR receptor and its target genes in thehippocampus of wild type mouseCompared with DMSO treated group, TO901317treatment significantly reduced theexpression of LXRβ and increased significantly the expression of Klf-9in thehippocampus of3months old wild-type mouse,. In addition, In TO901317treated group,ABCG1、 ABCA1and apoE expression in the hippocampus were also significantlyup-regulated.2．Effects of TO901317on the number of astrocytes and radial glial cells in the DGof the hippocampus of wild type mouse In3months old wild-type mouse, TO901317treatment resulted in the significantdecrease of GFAP positive cells in the DGwhereas in other regions of the hippocampusand other brain areas, the number of GFAP positive cells did not change significantly.TO901317treatment also lead to significant increase in the number of GFAP positive radialneurite number in DG-SGZ.In addition,.Moreover, TO901317treatment alsosignificantlyincreased the number of BLBP positive cells in the DG-SGZ of thehippocampal3．Effects of TO901317on the expression of LXR receptor and its target genesin.the hippocampus of AD mouseCompared with age matched wild type mice,the levels of ABCA1did not changesignificantly in the hippocampus of6months old APP/PS1double transgenic mice. Whentreated with TO901317, the ABCA1mRNA level were significantly increased in thehippocampus of6months old AD miceTO901317treatment also increased significantlythe Klf-9mRNA expressional level in the hippocampus of6months old AD mice4． Effects of TO901317on the number of astrocytes and radial glial cells in the DGof the hippocampus of AD mouseCompared with wt mice,the number of GFAP-positive astrocytes was significantlyincreased in the DG-SGZ of the AD mouse at6,10and13month old APP/PS1doubletransgenic mice.,TO901317treatment significantly reduced the number of GFAP–positiveastrocytes in DG-SGZ of AD mice.. Comapred with age matched wt mice, the number ofBLBP positive cells in the hippocampus of APP/PS1double transgenic mice wassignificantly reduced.In wt mice of6,10and13month old, the TO901317treatmentsignificantly increased the number of BLBP positive cells in the hippocampus after.Similarly, TO901317treatment significantly increased the number of BLBP positive cells inthe hippocampus of APP/PS1double transgenic mice at6,10and13month old.Conclusion：1．TO901317treatment significantly increased the number of GFAP positive radialglia like process and BLBP positive cells.in hippocampal DG-SGZ of WT and ADmice,and reduced the number of GFAP positive cells in the DG of the hippocampus, Itsuggests that LXR regulates the transforamtion of radial glia cells to astrocytes in theDG-SGZ. 2．LXR agonists upregulated the expression of LXR receptors,its target genes andKLF-9in the hippocampus of APP/PS1double transgenic mouse it suggests that LXR maybe involved in the regulation of adult hippocampal neurogenesis process through Klf-9.