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Fluids and Barriers of the CNS
Published in: Fluids and Barriers of the CNS 1/2018

Open Access 01-12-2018 | Research

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

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

Published in: Fluids and Barriers of the CNS | Issue 1/2018

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Abstract

Background

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.

Methods

Transcriptome-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.

Results

Pronounced 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.

Conclusions

Our 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.
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Metadata
Title
Comparative transcriptomics of choroid plexus in Alzheimer’s disease, frontotemporal dementia and Huntington’s disease: implications for CSF homeostasis
Authors
Edward G. Stopa
Keith Q. Tanis
Miles C. Miller
Elena V. Nikonova
Alexei A. Podtelezhnikov
Eva M. Finney
David J. Stone
Luiz M. Camargo
Lisan Parker
Ajay Verma
Andrew Baird
John E. Donahue
Tara Torabi
Brian P. Eliceiri
Gerald D. Silverberg
Conrad E. Johanson
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Fluids and Barriers of the CNS / Issue 1/2018
Electronic ISSN: 2045-8118
DOI
https://doi.org/10.1186/s12987-018-0102-9

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