Effect Of TYROBP On Neuroinflammation And Autophagy Through PI3K/AKT Signaling Pathway In Alzheimer’s Disease Mouse Model

Background:Alzheimer’s disease(AD),a progressive neurodegenerative disease characterized by learning and memory loss as well as behavioral and psychological symptoms of dementia,is a major type of cognitive impairment and dementia in older adults(≥ 65 years of age)worldwide.Extracellular β-amyloid protein(Aβ)deposition,neurofibrillary tangles(NFTs)from abnormal phosphorylation of intracellular tau protein and neuron loss are the typical pathological manifestations of AD.In recent years,more and more attention has been paid to the role of inflammatory factors and microglia in neuroinflammatory response in AD.TYROBP,also known as DAP 12,activates downstream signaling molecules by activating tyrosine kinase Syk through immunoreceptor tyrosine-based activation motifs(ITAM),and mediate the intracellular signaling of many receptors,such as Triggering receptor expressed on myreloid cells 2(TREM2)and CR3.TYROBP participate in the pathological process of AD by participating in various reactions such as inflammation and phagocytosis,but the specific mechanism remains unclear.Objective:To explore the effects of TYROBP on neuroinflammatory response and autophagy in APP/PS1 transgenic model mice.Methods:Eight-arm maze test and novel object recognition test were used to detect cognitive function;The activation of Nod-like receptor protein 3(NLRP3)inflammasome,microglia,neuron and astrocytes were assessed by immunofluorescence;The mRNA level of Tumor necrosis factor-α(TNF-α),Interleukin-6(IL-6)and Interleukin-1β(IL-1β)were measured by Real-time PCR;the protein expression level of NLRP3,cleaved Caspase-1,Sequestosome 1(SQSTM1),microtubule-associated protein light chain 3B Ⅱ(LC3B Ⅱ),TYROBP,Phosphoinositide 3-kinas(PI3K),p-PI3K,AKT and p-AKT were assayed by Western blot.Results:1.Compared with WT mice,neuroinflammatory was increased and autophagy was inhibited in the brain of APP/PS1 mice.2.Compared with WT mice,the expression of PI3K/AKT signaling pathway related protein and TYROBP protein was increased in the brain of APP/PS1 mice.3.In TYROBP-/-mice,neuroinflammatory was reduced,autophagy was activated,and the expression of PI3K/AKT signaling pathway related protein was reduced.Conclusion:TYROBP promotes inflammatory response and inhibits autophagy possibility by activating the PI3K/AKT signaling pathway,thus participate the occurrence and development of APP/PS1.