IL-17A Promotes Aβ Deposition,Aggravates Cognitive Impairment And Its Mechanism In APP/PS1 Transgenic Mice

Objective: Abnormal deposition of amyloid β(Aβ)is one of the main pathological features of Alzheimer’s disease(AD).The accumulation of Aβ leads to the abnormal aggregation,which exacerbates neurodegeneration.The accumulation of Aβ depends on the rate of production versus clearance.The clearance of Aβ was mainly mediated by glial cells,but the ability of glial cells to clear Aβ was impaired under continuous activation.Studies have shown that the expression of interleukin-17A(IL-17A)is significantly increased in the brain of AD patients and animal models,and lead to the deposition of Aβ and the activation of glial cells in the brain of AD animal models.However,the specific mechanism by which IL-17A induces Aβ deposition and whether it is involved in the overactivation of glial cells remains unclear.Therefore,the present study mainly explores the mechanism of IL-17A action on glial cells and the specific mechanism of Aβ deposition.Methods: 1.6-month-old male APP/PS1 mice and wild-type mice were randomly divided into two groups,the control group and the experimental group,respectively.Mice in the experimental group were injected with IL-17A(500ng/mouse)through tail vein for 10 days,and mice in the control group were injected with the same amount of PBS simultaneously.Then,the learning and cognitive abilities of mice were tested by behavioral experiments.2.After the animals sacrificed,Western blot,ELISA,IHC,IF and other experimental methods were used to determine the specific mechanism of IL-17A to induce Aβ deposition.3.Mice microglia cell line BV2 and mice astrocytes cell line D1 a was cultured in vitro and treated with 100ng/mL IL-17A.Western blot and IF methods were used to further explore the specific mechanism of IL-17A on Aβ deposition.Results: 1.IL-17A tail vein injection induced significantly upregulation of IL-17A level in the brain of mice,and the behavioral test results showed that IL-17A aggravated the cognitive and spatial learning impairment of APP/PS1 mice.2.In vivo studies showed that IL-17A significantly increased the loss of neurons by promoting the cleavage of caspase3;IL-17A significantly increased the deposition of Aβ in the brain of APP/PS1 mice.The mechanism involved that IL-17A upregulated BACE1 expression and increased Aβproduction,at the same time,IL-17A decreased LRP1 expression of glia cells and disrupted Aβ clearance.In addition,IL-17A significantly increased the inflammatory response in the brains of APP/PS1 mice and activated microglia and astrocytes.3.In vitro experiments showed that IL-17A inhibited the expression of LRP1 in BV2 and D1 a by inhibit p53 pathway,and the decreased LRP1 further induced the activation of NF-κB and JNK signaling pathway,which would promote the activation of glia cells.Conclusions: The results showed that IL-17A treatment could promote the expression of BACE1 and increased the production of Aβ,at the same time,IL-17A decrease glia cells LRP1 expression via inhibiting p53 signaling pathway and impaired Aβ clearance,thus aggravates the Aβ deposition.In addition,the downregulated LRP1 further induced the activation of JNK and NF-κB,which in turn activating the glial cells,promoting neuroinflammation and cytokines secretion.The Aβ deposition and neuroinflammation induced by IL-17A,induced caspase-dependent neuronal apoptosis,which aggravated the learning and cognitive dysfunction in APP/PS1 mice.