Dataset Information

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

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?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 oligomerization rate of A?42 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.

SUBMITTER: Raha-Chowdhury R

PROVIDER: S-EPMC6598012 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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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 Ruma R Henderson James W JW Raha Animesh Alexander AA Vuono Romina R Bickerton Anastasia A Jones Elizabeth E Fincham Robert R Allinson Kieren K Holland Anthony A Zaman Shahid H SH

Journal of Alzheimer's disease : JAD 20190101 1

<h4>Background</h4>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.<h4>Objective</h4>To investigate the genotype and phenotype of DS individuals in ...[more]

PMID: 30909239

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Project description:BackgroundThe cerebrospinal fluid (CSF), primarily generated by the choroid plexus (ChP), is the major carrier of the glymphatic system. The alternations of CSF production and the ChP can be associated with the Alzheimer's disease (AD). The present work investigated the roles of the ChP in the AD based on a proposed ChP image segmentation pipeline.MethodsA human-in-the-loop ChP image segmentation pipeline was implemented with intermediate and active learning datasets. The performance of the proposed pipeline was evaluated on manual contours by five radiologists, compared to the FreeSurfer and FastSurfer toolboxes. The ChP volume and blood flow were investigated among AD groups. The correlations between the ChP volume and AD CSF biomarkers including phosphorylated tau (p-tau), total tau (t-tau), amyloid-β42 (Aβ42), and amyloid-β40 (Aβ40) was investigated using three models (univariate, multiple variables, and stepwise regression) on two datasets with 806 and 320 subjects.ResultsThe proposed ChP segmentation pipeline achieved superior performance with a Dice coefficient of 0.620 on the test dataset, compared to the FreeSurfer (0.342) and FastSurfer (0.371). Significantly larger volumes (p < 0.001) and higher perfusion (p = 0.032) at the ChP were found in AD compared to CN groups. Significant correlations were found between the tau and the relative ChP volume (the ChP volume and ChP/parenchyma ratio) in each patient groups and in the univariate regression analysis (p < 0.001), the multiple regression model (p < 0.05 except for the t-tau in the LMCI), and in the step-wise regression model (p < 0.021). In addition, the correlation coefficients changed from - 0.32 to - 0.21 along with the AD progression in the multiple regression model. In contrast, the Aβ42 and Aβ40 shows consistent and significant associations with the lateral ventricle related measures in the step-wise regression model (p < 0.027).ConclusionsThe proposed pipeline provided accurate ChP segmentation which revealed the associations between the ChP and tau level in the AD. The proposed pipeline is available on GitHub ( https://github.com/princeleeee/ChP-Seg ).

Project description:BackgroundAlthough fibroblast growth factor (Fgf) signalling plays crucial roles in several developing and mature tissues, little information is currently available on expression of Fgf2 during early choroid plexus development and whether Fgf2 directly affects the behaviour of the choroid plexus epithelium (CPe). The purpose of this study was to investigate expression of Fgf2 in rodent and human developing CPe and possible function of Fgf2, using in vitro models. The application of Fgf2 to brain in vivo can affect the whole tissue, making it difficult to assess specific responses of the CPe.MethodsExpression of Fgf2 was studied by immunohistochemistry in rodent and human embryonic choroid plexus. Effects of Fgf2 on growth, secretion, aggregation and gene expression was investigated using rodent CPe vesicles, a three-dimensional polarized culture model that closely mimics CPe properties in vivo, and rodent CPe monolayer cultures.ResultsFgf2 was present early in development of the choroid plexus both in mouse and human, suggesting the importance of this ligand in Fgf signalling in the developing choroid plexus. Parallel analysis of Fgf2 expression and cell proliferation during CP development suggests that Fgf2 is not involved in CPe proliferation in vivo. Consistent with this observation is the failure of Fgf2 to increase proliferation in the tri-dimensional vesicle culture model. The CPe however, can respond to Fgf2 treatment, as the diameter of CPe vesicles is significantly increased by treatment with this growth factor. We show that this is due to an increase in cell aggregation during vesicle formation rather than increased secretion into the vesicle lumen. Finally, Fgf2 regulates expression of the CPe-associated transcription factors, Foxj1 and E2f5, whereas transthyretin, a marker of secretory activity, is not affected by Fgf2 treatment.ConclusionFgf2 expression early in the development of both human and rodent choroid plexus, and its ability to modulate behaviour and gene expression in CPe, supports the view that Fgf signalling plays a role in the maintenance of integrity and function of this specialized epithelium, and that this role is conserved between rodents and humans.

Project description:The choroid plexus (CP) consists of specialized ependymal cells and underlying blood vessels and stroma producing the bulk of the cerebrospinal fluid (CSF). CP epithelial cells are considered the site of the internal blood-cerebrospinal fluid barrier, show epithelial characteristics (basal lamina, tight junctions), and express aquaporin-1 (AQP1) apically. In this study, we analyzed the expression of aquaporins in the human CP using immunofluorescence and qPCR. As previously reported, AQP1 was expressed apically in CP epithelial cells. Surprisingly, and previously unknown, many cells in the CP epithelium were also positive for aquaporin-4 (AQP4), normally restricted to ventricle-lining ependymal cells and astrocytes in the brain. Expression of AQP1 and AQP4 was found in the CP of all eight body donors investigated (3 males, 5 females; age 74-91). These results were confirmed by qPCR, and by electron microscopy detecting orthogonal arrays of particles. To find out whether AQP4 expression correlated with the expression pattern of relevant transport-related proteins we also investigated expression of NKCC1, and Na/K-ATPase. Immunostaining with NKCC1 was similar to AQP1 and revealed no particular pattern related to AQP4. Co-staining of AQP4 and Na/K-ATPase indicated a trend for an inverse correlation of their expression. We hypothesized that AQP4 expression in the CP was caused by age-related changes. To address this, we investigated mouse brains from young (2 months), adult (12 months) and old (30 months) mice. We found a significant increase of AQP4 on the mRNA level in old mice compared to young and adult animals. Taken together, we provide evidence for AQP4 expression in the CP of the aging brain which likely contributes to the water flow through the CP epithelium and CSF production. In two alternative hypotheses, we discuss this as a beneficial compensatory, or a detrimental mechanism influencing the previously observed CSF changes during aging.

Dataset Information

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

Publications

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

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