The Orthologs Of TNF Superfamily Signaling Pathway Of Mammal Are Involved In The Process Of AD In A?_1-42Transgenic Caenorhabditis Elegans

Alzheimer disease(AD)is an age-dependent,complex neurodegenerative disease mainly caused dementia in humans,which is characterized by progressive cognitive impairment and memory loss.The hall mark of AD is extracellular senile plaques(SP)deposited by amyloid polypeptides(A?)in the cerebral cortex and neurofibrillary tangles(NFT)in neurons formed hyperphosphorylation of Tau.A large number of neurons are losted in the neocortex and hippocampus in the AD brain,which gradually leads to dementia.AD has become an urgent medical and social problem with the increasing the popualtion of ageing.some theories such as A? toxicity hypothesis,Tau protein toxicity hypothesis and inflammatory hypothesis and so on have been proposed.The inflammatory response was indicated to involve in the pathogenesis of AD through the inflammatory cytokines such as TNF-?,IL-1?,IL-10 and IL-17 induced by the transcription of active NF-?B.Tumor necrosis factor superfamily,as the important member of immune system,is a key siganling pathway to active inflammatory response.large number of studies supposed that the tumor necrosis factor superfamily members TNF-? and CD40 played a crucial role in AD pathogenesis.But there is no intact tumor necrosis factor superfamily signaling pathway in C.elegans.C.elegans has neither the orthologs of ligands and receptors in TNF superfamily signaling pathway nor the orthologs of adaper of TRADD or FADD,which interacts with TNFR with DD domain to induce apoptosis.C.elegans also lacks the ortholog of NF-?B,which has the reponsbility to inflammatory signaling pathway.But C.elegans has the orthologs(trf-1 and trf-2)of the adaper of TRAFs that are recruited by TNFR with TIM domain,which can active the downstream signling like p38,JNK and so on.Interestingly the transcription of gene F22E5.6 that is the ortholog of TNFAIP1 was increased the most significantly in C.elegans AD model.TNFAP1 is induced to express by TNF-? in human,while nematodes cannot express TNF-?.So a series of questions were proposed:which gene can regulate F22E5.6 in C.elegans?whether dose the imcomplete TNF superfamily signaling pathway involve in the toxicity induced by A[3?If the imcomplete TNF superfamily-signaling pathway does,what mechanism can lead to the toxicity of A? under lacking the inflammtory signaling pathway in C..elegans?What is the upstream and dowmstream pathway of TNF superfamily signaling pathway?According to the above questions,we carried out the research:1.Our data revealed that the imcomplete TNF superfamily signaling pathway including the gene trf-1,pmk-3,vhp-1 and src-2 were involved the toxicity induced by A? through RNAi technology and knockout of genes in C.elegans,and src-2 was located on the upstream of p38 siganling pathway to phosphorylate pmk-3.2.Although both ligands and receptors are abscent in C.elegans,our study indicated that tol-1 which is the only one ortholog of toll-like recepers family in C.elegans was involved in the toxicity induced by A? through the imcomplete TNF superfamily-signaling pathway.And tol-1 overexpression showed that tol-1 as the upstream gene could regulate trf-1/src-2/pmk-3.In addition,tol-1 was involved in regulating the transcription of F22E5.6 unregulated by A?1-42 in C.elegans.3.What is the downstream if the toxicity of A?1-42 is not induced by inflammatory signaling pathway actived by NF-?B through the imcomplete TNF superfamily-signaling pathway in C.elegans?RNAi assay,qPCR and western blot test revealed that aap-1,akt-2 and let-363 were involved in the paralysis of AD worms.And the phosphorylation of Akt-2 was regulated by Src-2,which means that PI3K/AKT/mTOR signaling pathway as the downstream of the imcomplete TNF superfamily signaling pathway to lead to the toxicity of A?1-42.4.mTOR signaling is the core to regulate the growth and metabolism of cell,which can affect the mitochondria directly.Does A?1-42 act on the mitochondria through Src-2/Akt-2/let-363?Our research found that A?1-42 caused the increasing of ROS,depression of mitochondrial oxidative phosphorylation,and the fragment of mitochondria.While knockdown of src-2 or pmk-3 could decline level of ROS and enhance the mitochondrial oxidative phosphorylation,delay the mitochondria fragment and increase the mitophage.So all of these data indicated that A?1-42 led to mitochondrial dysfunction through the imcomplete TNF superfamily-signaling pathway in C.elegans.Our paper illuminated the mechanism of AD caused by the imcomplete TNF superfamily-signaling pathway in C.elegans.And the innovation of the investigation were concluded as below:1.The imcomplete TNF superfamily-signaling pathway was involved in the pathogeneosis of A?1-42 in C.elegans,which was significantly different from the pathway of mammal.2.The imcomplete TNF superfamily sigaling pathway caused mitochondrial dysfunction to lead to pathogeneosis in AD worms.