Choroid Plexus Acts as Gatekeeper for TREM2, Abnormal Accumulation of ApoE, and Fibrillary Tau in Alzheimer's Disease and in Down Syndrome Dementia.

Ruma Raha-Chowdhury,Shahid H Zaman,Robert Fincham,Kieren Allinson,James W Henderson,Animesh Alexander Raha,Anthony Holland,Elizabeth Jones,Anastasia Bickerton,Romina Vuono

doi:10.3233/jad-181179

Abstract

Background:Genetic factors that influence Alzheimer’s disease (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 may compromise the blood-cerebrospinal fluid (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 HLA-DR were analyzed by SNP analysis in DS participants (n = 47) and controls (n = 50). The corresponding plasma protein levels were measured by ELISA. Postmortem brains from DS, AD, and age-matched controls were analyzed by immunohistochemistry.Results:Haplotype analysis showed that individuals with Tau H1/H1 and ApoE ɛ4 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 oligomerization rate of Aβ42 and impair tau trafficking, leading to AD pathology. We have identified a high-risk haplotype: ApoE ɛ4, 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.

Highlights

Down syndrome (DS) is the most common human aneuploidy associated with intellectual disability and early neurodegeneration
It was reported that the haplotypes of both Apolipoprotein E (ApoE) and Tau have been linked to Alzheimer’s disease (AD) and other neurodegenerative diseases including in frontotemporal dementia, Huntington’s disease, and Parkinson’s disease
In this paper in the DS cohort, we have reported that individuals with a Tau H1/H1 and ApoE ␧4 genotype were more prevalent among DS participants (21%) who had an earlier diagnosis of dementia compared to ApoE ␧4 and Tau H1/H2 haplotypes (6%)

Summary

Introduction

Down syndrome (DS) is the most common human aneuploidy associated with intellectual disability and early neurodegeneration. Dysfunction of amyloid-␤ protein precursor (A␤PP) processing is believed to be the key upstream factor in the pathogenesis of AD [6], neuroinflammation and activation of innate immunity are considered early events in the genesis of AD and in DS dementia. Genetic factors that influence Alzheimer’s disease (AD) risk include mutations in TREM2 and allelic variants of Apolipoprotein E, influencing AD pathology in the general population and in Down syndrome (DS). Methods: To assess allele frequency and haplotype associations ApoE, Tau, TREM2, and HLA-DR were analyzed by SNP analysis in DS participants (n = 47) and controls (n = 50). 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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