Comparative transcriptomics of choroid plexus in Alzheimer\u2019s disease, frontotemporal dementia and Huntington\u2019s disease: implications for CSF homeostasis

Edward G Stopa,Lisan Parker,Alexei A Podtelezhnikov,Gerald D Silverberg,Tara Torabi,Conrad E Johanson,Miles C Miller,Keith Q Tanis,John E Donahue,Eva M Finney,Ajay Verma,Andrew Baird,Luiz M Camargo,Brian P Eliceiri,David J Stone,Elena V Nikonova

doi:10.1186/s12987-018-0102-9

Abstract

BackgroundIn Alzheimer’s disease, there are striking changes in CSF composition that relate to altered choroid plexus (CP) function. Studying CP tissue gene expression at the blood–cerebrospinal fluid barrier could provide further insight into the epithelial and stromal responses to neurodegenerative disease states.MethodsTranscriptome-wide Affymetrix microarrays were used to determine disease-related changes in gene expression in human CP. RNA from post-mortem samples of the entire lateral ventricular choroid plexus was extracted from 6 healthy controls (Ctrl), 7 patients with advanced (Braak and Braak stage III–VI) Alzheimer’s disease (AD), 4 with frontotemporal dementia (FTD) and 3 with Huntington’s disease (HuD). Statistics and agglomerative clustering were accomplished with MathWorks, MatLab; and gene set annotations by comparing input sets to GeneGo (http://www.genego.com) and Ingenuity (http://www.ingenuity.com) pathway sets. Bonferroni-corrected hypergeometric p-values of < 0.1 were considered a significant overlap between sets.ResultsPronounced differences in gene expression occurred in CP of advanced AD patients vs. Ctrls. Metabolic and immune-related pathways including acute phase response, cytokine, cell adhesion, interferons, and JAK-STAT as well as mTOR were significantly enriched among the genes upregulated. Methionine degradation, claudin-5 and protein translation genes were downregulated. Many gene expression changes in AD patients were observed in FTD and HuD (e.g., claudin-5, tight junction downregulation), but there were significant differences between the disease groups. In AD and HuD (but not FTD), several neuroimmune-modulating interferons were significantly enriched (e.g., in AD: IFI-TM1, IFN-AR1, IFN-AR2, and IFN-GR2). AD-associated expression changes, but not those in HuD and FTD, were enriched for upregulation of VEGF signaling and immune response proteins, e.g., interleukins. HuD and FTD patients distinctively displayed upregulated cadherin-mediated adhesion.ConclusionsOur transcript data for human CP tissue provides genomic and mechanistic insight for differential expression in AD vs. FTD vs. HuD for stromal as well as epithelial components. These choroidal transcriptome characterizations elucidate immune activation, tissue functional resiliency, and CSF metabolic homeostasis. The BCSFB undergoes harmful, but also important functional and adaptive changes in neurodegenerative diseases; accordingly, the enriched JAK-STAT and mTOR pathways, respectively, likely help the CP in adaptive transcription and epithelial repair and/or replacement when harmed by neurodegeneration pathophysiology. We anticipate that these precise CP translational data will facilitate pharmacologic/transgenic therapies to alleviate dementia.

Highlights

In Alzheimer’s disease, there are striking changes in cerebrospinal fluid (CSF) composition that relate to altered choroid plexus (CP) function
The Alzheimer’s disease (AD) group had the highest number of differentially expressed probe sets likely due, at least in part, to the higher number of AD subjects compared to Huntington’s disease (HuD) and frontotemporal dementia (FTD). 3935 (7%) out of the 57,060 probe sets on the array were differentially expressed [p < 0.01, false discovery rate (FDR) = 14%] between AD and Ctrl subjects, while 1287 (FDR = 44%) and 2136 (FDR = 27%) probe sets were regulated with p < 0.01 in HuD and FTD, respectively (Fig. 1a, b, Additional file 2: Table S2)
In order to validate these findings with different subjects and gene expression platforms, we compared the results in whole CP to those obtained by Bergen et al in laser-dissected CP epithelial cells from control and AD subjects [26]

Summary

Introduction

In Alzheimer’s disease, there are striking changes in CSF composition that relate to altered choroid plexus (CP) function. Studying CP tissue gene expression at the blood–cerebrospinal fluid barrier could provide further insight into the epithelial and stromal responses to neurodegenerative disease states. BCSFB alterations such as choroid epithelial cell atrophy, stromal fibrosis, vascular thickening, tight junction (claudin-5) downregulation, and basement membrane thickening are associated with AD pathology [20]. These changes in the epithelial–stromal nexus likely affect secretion and transport, resulting in diminished CSF turnover and modified neuroimmune regulation. Oxidative stressors in AD and other dementias may differentially impact CP’s ability to synthesize/transport proteins/hormones, and to regulate cellular/CSF metabolites such as methionine/homocysteine [23], Aβ/tau [24], and creatine/creatinine [25]

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Results

Discussion

Conclusion