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TREM2, Tau and ApoE in choroid plexus in AD pathology

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Raha-Chowdhury, Ruma 
Henderson, James W 
Raha, Animesh Alexander 
Vuono, Romina 


Background: Genetic factors that influence AD risk include mutations in TREM2 and allelic variants of Apolipoprotein-E, influencing AD pathology in the general population and in Down syndrome (DS). Evidence shows that dysfunction of the choroid plexus (CP) may compromise the blood-CSF barrier, altering secretary, transport and immune function that can affect AD pathology Objective: To investigate the genotype and phenotype of DS individuals in relation to choroid plexus damage and blood-CSF barrier leakage to identify markers that could facilitate early diagnosis of AD in DS. Methods: To assess allele frequency and haplotype associations ApoE, Tau, TREM2 and HLADR were analysed by SNP analysis in DS participants (n=47) and controls (n = 50). The corresponding plasma protein levels were measured by ELISA. Post-mortem brains from DS, AD and age matched controls were analysed by immunohistochemistry. Results: Haplotype analysis showed that individuals with Tau H1/H1 and ApoE 4 genotypes were more prevalent among DS participants with an earlier diagnosis of dementia (17%) compared to H1/H2 haplotypes (6%). Plasma TREM2 levels decreased whereas phospho-Tau levels increased with age in DS. In AD and DS brain insoluble Tau and ApoE were found to accumulate in the choroid plexus. Conclusion: Accumulation of Tau and ApoE in the choroid plexus may increase the oligomerisation rate of Aβ42 and impair Tau trafficking, leading to AD pathology. We have identified a high-risk haplotype: ApoE 4, Tau/ H1 and TREM2/T, that manifests age-related changes potentially opening a window for treatment many years prior to the manifestation of the AD dementia.



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Journal of Alzheimer's Disease

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IOS Press
Medical Research Council (G1002252)
MRC (G1002252/1)
Alzheimer's Research UK (ARUK-PG2015-23)