Investigation On The Association Between CR1 And AD Biomarkers And The Role Of CR1 In AD-related Tau Pathology

Alzheimer's disease(AD)is the most common form of dementia,and it has already affected over 35.6 million people worldwide;moreover,the number will rise to 65.7 million by 2030.AD is a multifactorial disease,such as age,positive history and genetic factors.Of note,genetics has been widely accepted to play a significant role in late onset AD(LOAD)with heritability estimates of 60 to 80%,To date,several genome-wide association studies(GWAS)have revealed a significant relation between AD and single nucleotide polymorphisms(SNPs)in nine novel AD loci.Among these identified genes,the complement component(3b/4b)receptor 1 gene(CR1)is confirmed as one of the most important genetic susceptibility loci in AD.After the first study revealed CR1 SNPs linked closely to AD risk,CR1 is revealed to show a close relation of AD susceptibility across different ethnic groups and districts.Allowing for the strong association between CR1 and AD susceptibility,it emerges necessary to disclose the concrete role of CR1 in AD pathology.However,few studies were performed to explore the relation between common variants in CR1 and other AD-related biomarkers.Hence,in the first part of this study,we evaluated the potential role of CR1 common variants in AD-related pathology by assessing neuroimaging biomarkers and cerebrospinal fluid(CSF)proteins.The accumulation of neurotoxic amyloid ?(A?)and tau-associated neurofibrillary tangles(NFT)are two hallmarks of AD pathology.The current studies mainly disclosed that CR1 influenced on AD pathology by modulating the metabolism of amyloid protein.Since hyperphosphorylated tau is an identical pathological feature of AD,it would make a difference to disclose the effect of CR1 on taupathy.Crl-related protein Y(Crry),a specific rodent gene,which encodes an important cell-surface regulator of complement that shares great similar protein sequences and functions of human CR1.It is believed that human CR1 gene evolved from the Crry gene for sequence homology and the support of the locations of the Crry/CR1 genes.Allowing for these evidences,it has been widely accepted Crry in murine models as the replace of CR1 in human.In the second part of this study,our group provides first evidence to explore the potential mechanism of CR1 on AD-related taupathy via testing the role of Crry in murine models.In summary,we hope our study would bring new further of the early diagnosis and treatment in AD.PART I Association between CR1 genetic variants and AD biomarkersAims:To evaluate the role of CR1 common variants in AD pathology by assessing neuroimaging biomarkers and CSF proteins.Materials and Methods:812 individuals from ADNI database who fulfilled quality control for genotype data were enrolled,including 48 AD,483 MCI,and 281 NC.Eight SNPs(rs10779339,rs12034383,rs2025935,rs3737002,rs3838361,rs4844609,rs4844610,and 6691117)were enrolled which have been verified by GWAS studies,large case-control trials or other experimental studies.We included three neuroimaging measurements,florbetapir retention on florbetapir 18F amyloid positron emission tomography(AV45-PET),regional volume on MRI,and cerebral metabolic rate for glucose on 18F-fluorodeoxyglucose PET(FDG-PET).CSF proteins,including A?42,t-tau and p-tau,were examined on the multiplex xMAP Luminex platform(Luminex Corp,Austin,TX)with Innogenetics(INNOBIA AlzBio3;Ghent,Belgium;for research use only reagents)immunoassay kit-based reagents.Results:Our results indicated rs4844609 showed a significant positive association with the level of tracer retention on amyloid PET imaging in cingulated,frontal,parietal,and temporal.Moreover,rs4844609 mainly effected MCI and NC population.Rs12034383 is demonstrated negatively associated with the volume of left and right middle temporal.Rs3737002 shows significant positive connection with the left and right middle temporal.In addition,a negative association is confirmed between rs669117 and left middle temporal.Rs10779339 was proved to significantly decrease the metabolism rate of glucose in the right temporal on FDG-PET imaging,and the significant results were mainly in AD and MCI cohorts.No significant associations were confirmed between included CR1 genetic variants and CSF proteins in a multiple linear regression mode.Conclusion:Our study indicated that a close association between CR1 common variants and AD pathology,such A? deposition,brain structure,and glucose metabolism during AD progression.PART ? Role of complement receptor 1 mediated mechanisms in Alzheimer's Disease-related tau pathologyAims:To investigate the possible mechanisms of CR1 on AD-related taupathy via testing the role of Crry in a murine AD transgenic model.Materials and Methods:In this study,we used P301S transgenic mice,a classic animal model of AD,and manipulated Crry expression using a lentiviral strategy to reveal its effects.We assessed the levels of hyperphosphorylated tau,tau kinase,tauphosphatase and complement system proteins via western blotting or immunohistochemistry.We observed the role of Crry in cognitive impairment via the Morris water maze test.The expression of neroinflamation cytokines were investgated by qRT-PCR.Results:Finally,we discovered that when down-regulating the expressions of Crry,tau hyperphosphorylation and cognitive functions deficiency were significantly alleviated via modulating neuroinflammation and complement system in AD context.Conclusion:These findings highlight the role of CR1 in AD-related taupathy and suggest that modulating CR1 may be promising therapeutic targets for AD.