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Choroid plexus acts as gatekeeper for TREM2, abnormal accumulation of ApoE, and fibrillary tau in Alzheimer's disease and in down syndrome dementia

Raha-Chowdhury, R., Henderson, J.W., Raha, A.A., Vuono, R., Bickerton, A., Jones, E., Fincham, R., Allinson, K., Holland, A., Zaman, S.H. and others. (2019) Choroid plexus acts as gatekeeper for TREM2, abnormal accumulation of ApoE, and fibrillary tau in Alzheimer's disease and in down syndrome dementia. Journal of Alzheimer's Disease, 69 (1). pp. 91-109. ISSN 1387-2877. (doi:10.3233/JAD-181179) (KAR id:79834)

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http://dx.doi.org/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 ϵ4 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 ϵ4, 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.

Item Type: Article
DOI/Identification number: 10.3233/JAD-181179
Uncontrolled keywords: amyloid beta protein1-42; apolipoprotein E; apolipoprotein E2; apolipoprotein E3; apolipoprotein E4; DNA; HLA DR antigen; plasma protein; tau protein; triggering receptor expressed on myeloid cells 2, adult; aged; Alzheimer disease; Article; autopsy; blood cerebrospinal fluid barrier; brain tissue; choroid plexus; clinical article; clinical assessment; clinical evaluation; comparative study; controlled study; dementia; disease association; Down syndrome; early diagnosis; entorhinal cortex; enzyme linked immunosorbent assay; female; gene frequency; gene mutation; genetic association; genetic risk; genotype; haplotype; high risk patient; hippocampus; human; human tissue; immunohistochemistry; longitudinal study; male; middle aged; neuroimaging; neuroprotection; nuclear magnetic resonance imaging; phenotypic variation; positron emission tomography; priority journal; protein blood level; protein expression; risk assessment; risk factor; senile plaque; single nucleotide polymorphism
Divisions: Divisions > Division of Natural Sciences > Medway School of Pharmacy
Depositing User: Romina Vuono
Date Deposited: 29 Jan 2020 10:05 UTC
Last Modified: 16 Feb 2021 14:11 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/79834 (The current URI for this page, for reference purposes)
Vuono, R.: https://orcid.org/0000-0002-5162-3422
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