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

• Published in: Fluids and barriers of the CNS Vol. 15; no. 1; p. 18
• Main Authors: Stopa, Edward G, Tanis, Keith Q, Miller, Miles C, Nikonova, Elena V, Podtelezhnikov, Alexei A, Finney, Eva M, Stone, David J, Camargo, Luiz M, Parker, Lisan, Verma, Ajay, Baird, Andrew, Donahue, John E, Torabi, Tara, Eliceiri, Brian P, Silverberg, Gerald D, Johanson, Conrad E
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 31.05.2018; BioMed Central; BMC
• Subjects: Adult; Advertising executives; Aged; Aged, 80 and over; Alzheimer Disease - metabolism; Alzheimer's disease; Blood–CSF barrier inflammatome; Brain research; Cadherin-mediated adhesion; Cadherins; Cell adhesion; Cerebrospinal fluid; Choroid plexus; Choroid Plexus - metabolism; Choroid plexus transcriptome; Comparative analysis; Dementia; Dementia disorders; Disease; DNA microarrays; Female; Fluids; Frontotemporal dementia; Frontotemporal Dementia - metabolism; Gene Expression; Genes; Genetic translation; Homeostasis; Homeostasis - physiology; Homocysteine; Humans; Huntington Disease - metabolism; Huntingtons disease; Immune response; Interferon; Interleukins; Janus kinase/signal transducers and activators of transcription (JAK-STAT); Male; Metabolites; Methionine; Microarray Analysis; Middle Aged; Neurodegeneration; Neurodegenerative diseases; Neuroimmune CSF regulation; Peroxisome-proliferator-activated receptor (PPAR); Proteins; Ribonucleic acid; RNA; TOR protein; Transcription; Transcriptome; Vascular endothelial growth factor; Ventricle; Blood–CSF barrier inflammatome; Peroxisome-proliferator-activated receptor (PPAR); Choroid plexus methionine; Choroid plexus transcriptome; CSF homocysteine; Neuroimmune CSF regulation; Cadherin-mediated adhesion; Janus kinase/signal transducers and activators of transcription (JAK-STAT); LRP-1; Vascular endothelial growth factor; Mechanistic target of rapamycin (mTOR)
• ISSN: 2045-8118; 2045-8118
• DOI: 10.1186/s12987-018-0102-9

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. 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. 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. 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.