Study On The Differentiation Of Oligodendrocyte In The Juvenile AD Model Mouse Cortex

Oligodendrocytes(OLs)are the main glial cells in the central nervous system.Mature OLs enclose the axons of neurons in spiral layers to form myelin sheath to ensure rapid and stable transmission of nerve impulses.Abnormal development of OLs or loss of myelin sheath is associated with a number of neurological disorders such as multiple sclerosis,depression,and Alzheimer’s disease(AD).In the course of AD,either the deposition of Aβ or the hyperphosphorylation of Tau protein will directly affect the function of neurons,and the damage of neurons will cause demyelination and axon loss.In addition,ischemia,oxidative stress,excitatory toxicity,and iron overload can also affect the development of oligodendrocytes,which in turn can cause neuronal damage.It can be said that OLs or abnormal myelin development plays an important role in the pathology of AD and is expected to be a potential therapeutic target.It was found that OLs and myelin were affected in mice with various AD models before amyloid deposition and pathological changes in the cerebral cortex appeared.A recent study found that myelin loss occurred in both Aβdeposited and non-deposited areas of the APP/PS1 brain in old AD model mice,and cell experiments demonstrated that Aβ does not affect the differentiation of OLs.Therefore,we speculated that AD mice may develop abnormal myelin development during adolescence and play an important role in the pathological process of AD.In this thesis,the brain of APP/PS1 in AD model mice in early postnatal development was studied to investigate the changes of oligodendrocyte and its myelination.Our study found that,compared with wild-type mice,OLs development was hindered and myelination was reduced in the cerebral cortex of APP/PS1 mice as early as 15 days after birth,and such oligodendrocyte development and myelination abnormalities were still maintained until the P30 stage,but OLs proliferation and apoptosis were not abnormal.Meanwhile,after continuous coronal section comparison,we also found that OLs differentiation in the cerebral cortex of APP/PS1 mice at the early stage of development was brain region specific,and OLs differentiation in the frontal lobe of APP/PS1 mice was mainly concentrated in the primary motor cortex and secondary motor cortex.In the cortex above the hippocampus,OLs differentiation was blocked mainly in the barrel-field area of primary somatosensory cortex,trunk area of primary somatosensory cortex and parietal association cortex.These regions are involved in motor execution and control,somatosensory reception integration,spatial relationship and working memory.In addition,transcriptome sequencing was performed on cerebral cortex tissues of APP/PS1 mice and wild-type mice at the P15 stage.The results showed that the transcription levels of 203 genes in APP/PS1 mice were changed during P15 compared with wild-type mice,of which 75 genes were up-regulated and 128 genes were down-regulated.Consistent with our above results,sequencing results showed that many genes related to OLs differentiation(Mbp,Myrf,Cnp,Mog,etc.)were significantly down-regulated.Through enrichment analysis of KEGG pathway of differentially expressed genes,we found significant changes in extracellular receptor interaction pathway,PI3 K signaling pathway,tyrosine metabolism and other signaling pathways,among which many genes such as Egf and Tlr4 have been proven to be related to OLs differentiation.These results provide new ideas and directions for the pathogenesis,early diagnosis and intervention of Alzheimer’s disease.