The Role,molecular Mechanism And Therapeutic Intervention Exploration Of PDCD4 In Alzheimer’s Disease

Alzheimer’s disease(AD)is a common and progressive neurodegenerative disease.Its main pathological changes are amyloid plaques formed by insoluble β-amyloid(Aβ)deposition,neurofibrillary tangles(NFTs)formed by hyperphosphorylated Tau protein(p-Tau),and neuronal damage.Due to its unclear pathogenesis,there is no effective treatment.Programmed cell death protein 4(PDCD4)is an important protein translation inhibitor that was initially considered to be a tumor suppressor gene.Later,it was found to play an important role in obesity,atherosclerosis,depression and other diseases.However,the role of PDCD4 in AD remains unclear.Objective:(1)To demonstrate that PDCD4 plays an important role in AD development;(2)To explore the molecular mechanism of PDCD4 in the development of AD;(3)Design intervention methods with PDCD4 as the target to analyze the feasibility of treating AD.Methods:(1)The human AD gene expression database was used to analyze the relationship between PDCD4 expression and AD;(2)APP/PS1 double transgenic AD mouse model,PDCD4 knockout mouse model,overexpression system,memory and cognitive behavior detection,immunofluorescence staining,and Western Blot were used to determine the relationship between PDCD4 and AD;(3)The molecular mechanism of PDCD4 was analyzed by Western Blot,qPCR,IP and other molecular biological methods;(4)The small interfering RNA of PDCD4(siPDCD4)was designed and modified to analyze the feasibility of treating AD through peripheral administration.Results:(1)The expression level of PDCD4 was increased in the brains of AD patients and AD mice,suggesting that PDCD4 was related to the development of AD;(2)After knocking out PDCD4,the cognitive impairment of AD mice was improved,and the accumulation of Aβ and p-Tau was decreased,while the overexpression of PDCD4 exacerbated the cognitive impairment of AD mice;(3)Through mechanism exploration,it was found that PDCD4 could regulate the expression level of CCAAT/enhancer binding protein β(C/EBPβ),a new target of AD.After silencing or knocking out PDCD4,the protein level of C/EBPβ was down-regulated,while the overexpression of PDCD4 promoted the expression of C/EBPβ;(4)PDCD4 inhibited the ubiquitination degradation of C/EBPβ by directly inhibiting the expression of the ubiquitin ligase COP1,leading to the up-regulation of C/EBPβ expression,further activating the C/EBPβ-AEP pathway,promoting the production and accumulation of Aβ and p-Tau,and exacerbating AD.However,the overexpression of COP1 improved the cognitive impairment and hippocampal pathological changes induced by PDCD4 in mice;(5)Intracerebral-targeted PDCD4 small interfering RNA(RVG/siPDCD4)could cross the blood-brain barrier into the brain through intraperitoneal injection,effectively improve cognitive impairment and reduce the accumulation of p-Tau in AD mice.Conclusion/Innovation and significance:(1)PDCD4 can promote the development of AD and may become a new target for AD therapy;(2)Revealed the mechanism by which PDCD4 inhibited the expression of ubiquitin ligase COP1,reduced the ubiquitination degradation of C/EBPβ,up-regulated its expression and activated the C/EBPβ-AEP pathway,promoted the deposition of Aβ and p-Tau,and then accelerated the pathological process of AD;(3)Intracerebral-targeted PDCD4 small interfering RNA(RVG/siPDCD4)has a therapeutic effect on AD,providing a new idea for the development of AD drugs.Limitations:Due to time constraints,the pathological detection of some in vivo experiments is not yet perfect.