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/lp/springer_journal/comparative-transcriptomics-of-choroid-plexus-in-alzheimer-s-disease-12LQXz71L2
- Publisher
- Springer Journals
- Copyright
- Copyright © 2018 by The Author(s)
- Subject
- Biomedicine; Neurosciences; Hematology; Neurobiology
- eISSN
- 2045-8118
- DOI
- 10.1186/s12987-018-0102-9
- pmid
- 29848382
- Publisher site
- See Article on Publisher Site
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 fur - ther 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. geneg o.com) and Ingenuity (http://www.ingen uity.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 char- acterizations 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, *Correspondence: Conrad_Johanson@brown.edu Edward G. Stopa and Keith Q. Tanis contributed equally to this work Departments of Neurosurgery and Pathology (Neuropathology Division), Rhode Island Hospital, The Warren Alpert Medical School, Brown University, Providence, RI, USA Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Stopa et al. Fluids Barriers CNS (2018) 15:18 Page 2 of 10 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. Keywords: Choroid plexus transcriptome, Neuroimmune CSF regulation, Blood–CSF barrier inflammatome, Janus kinase/signal transducers and activators of transcription (JAK-STAT ), Peroxisome-proliferator-activated receptor (PPAR), Cadherin-mediated adhesion, Vascular endothelial growth factor, LRP-1, Choroid plexus methionine, CSF homocysteine, Mechanistic target of rapamycin (mTOR) Background and Huntington’s disease (HuD). Our working hypoth- The choroid plexus (CP) is a CNS secretory tissue within esis anticipated: (i) common denominators of altered CP the cerebroventricular system consisting of a vascular expression in the three diseases, as well as (ii) differential stroma surrounded by epithelium [1, 2]. Although the expression patterns due to disease-specific alterations in primary function of choroidal tissue is to produce and neural metabolites, that by ‘homeostatic feedback sign- regulate cerebrospinal fluid (CSF), it also importantly aling’ via volume transmission from brain to CSF to CP, provides a permeability-regulating blood–CSF barrier could uniquely modulate gene expression at the BCSFB. (BCSFB) [3]. Other additional roles of CP relate to CNS Investigating CP tissue gene expression in various CNS wound repair [4], sex hormone modulation of BCSFB- diseases likely informs on diverse BCSFB adjustments to CNS [5], catabolite detoxification [6], ion regulation [7], neurodegeneration. Bergen et al. [26] focused on gene a selective leukocyte gate [8], and CSF–brain neuroim- expression changes by CP epithelial cells in AD. In this mune homeostasis, including interferon actions [9–13]. study, we analyze CP tissue responses (epithelium plus Recently, the BCSFB tissue has been examined for unique stroma) by providing profiles of mRNA changes. The CP changes in diverse disorders: mitochondrial dis- altered expression profiles in AD, FTD and HuD are eases [14], multiple sclerosis/experimental autoimmune discussed in relation to restorative homeostatic mecha- encephalitis [15, 16], schizophrenia [17], acute response nisms, as well as to chronic BCSFB damage and disrupted to peripheral immune challenge [18], normal pressure CSF–brain homeostasis. hydrocephalus [19], and Alzheimer’s disease (AD) [20, 21]. Methods Analyzing the transformed CP tissue composition and Project approval, sample collection and demographics pathophysiologic functions in neurodegeneration eluci- This research with banked specimens of human CP tis - dates specific metabolic/secretory processes underlying sue was approved by the Institutional Review Board CSF–CNS disease pathogenesis [22]. BCSFB alterations for Clinical Research at Lifespan, Rhode Island Hospi- such as choroid epithelial cell atrophy, stromal fibrosis, tal, Providence, RI. Post-mortem tissue samples from 6 vascular thickening, tight junction (claudin-5) down- healthy Ctrls of mean age 60 years, mean post-mortem regulation, and basement membrane thickening are interval (PMI) 22 h; and from 7 patients with advanced associated with AD pathology [20]. These changes in the AD (Braak and Braak stage III–VI, 80 years, PMI 17 h), epithelial–stromal nexus likely affect secretion and trans - 4 FTD (72 years, PMI NA) and 3 HuD (71 years, PMI port, resulting in diminished CSF turnover and modified 19 h), were snap frozen in liquid N and stored at − 80 °C neuroimmune regulation. Neuroimmune phenomena in the Brown University Brain Tissue for Neurodegenera- in the CP and/or CSF include adjustments in the level tive Disorders Resource Center until processed. Demo- of proteins (e.g., neurotrophins, interferons and growth graphic and disease data for the individual controls and factors), cytokines, and certain immune cells [12, 22]. patients are presented in Table 1. Oxidative stressors in AD and other dementias may also differentially impact CP’s ability to synthesize/transport Microarray design and analysis proteins/hormones, and to regulate cellular/CSF metabo- RNA from CP was extracted using TRIzol reagent in lites such as methionine/homocysteine [23], Aβ/tau [24], accordance with instructions by manufacturer (Thermo- and creatine/creatinine [25]. Fisher, Grand Island, NY). Isolated RNA samples were This investigation at the Brown University Medical assayed for quality via the Agilent RNA 6000 Pico Kit School, in collaboration with Merck & Co., analyzed on Agilent Bioanalyzer (Santa Clara, CA) and RNA gene expression in CP tissues from late-stage Alzhei- yield via Quanti-iT RiboGreen RNA Assay Kit (Thermo- mer patients, for comparison with control subjects (Ctrl) Fisher). Samples were amplified and labeled using an and two other diseases: frontotemporal dementia (FTD) automated version of the NuGEN Ovation WB protocol Stopa et al. Fluids Barriers CNS (2018) 15:18 Page 3 of 10 Table 1 Demographic and clinical data of choroid plexus p-values (expectation (e)-values) of <0.1 were considered samples collected a significant overlap between sets. Sample ID # Diagnosis Age Sex PMI Results CP_CTR_007 Control 62 M 23.9 We first compared the genome-wide differences in gene CP_CTR_008 Control 55 F 29 expression between diseased and Ctrl CP. p-value distri- CP_CTR_009 Control 37 M 18.7 butions from T-test comparisons, between the Ctrl group CP_CTR_010 Control 64 M 25.8 and each of the neurodegenerative disease groups (AD, CP_CTR_011 Control 69 F 12.3 HuD, FTD), revealed significant effects on the CP tran - CP_CTR_012 Control 70 M N/A scriptome in each of the 3 diseases (Fig. 1a, Additional CP_ALZ_015 AD (Braak III–IV ) 74 F 15 file 2: Table S2). The AD group had the highest number CP_ALZ_017 AD (severe Braak V–VI) 84 F N/A of differentially expressed probe sets likely due, at least CP_ALZ_018 AD (severe Braak V–VI) 84 M N/A in part, to the higher number of AD subjects compared CP_ALZ_019 AD (severe + Lewy body disease) 84 F N/A to HuD and FTD. 3935 (7%) out of the 57,060 probe sets CP_ALZ_020 AD (severe Braak V–VI) 89 M N/A on the array were differentially expressed [p < 0.01, false CP_ALZ_022 AD (severe Braak V–VI) 73 M 24.5 discovery rate (FDR) = 14%] between AD and Ctrl sub- CP_ALZ_023 AD (severe Braak V–VI) 70 M 10.8 jects, while 1287 (FDR = 44%) and 2136 (FDR = 27%) CP_FTD_024 FTD 76 M N/A probe sets were regulated with p < 0.01 in HuD and CP_FTD_025 FTD and motor neuron disease 75 F N/A FTD, respectively (Fig. 1a, b, Additional file 2: Table S2). CP_FTD_026 FTD Pick’s disease 58 M N/A Despite the limited statistical power and resulting high CP_FTD_027 FTD 80 F N/A false discovery rates in the HuD and FTD comparisons, CP_HuD_029 HuD (grade IV ) 68 M 30.1 there was a large degree of overlap in the genes identified CP_HuD_030 HuD (grade IV ) 65 F 3.5 in each of the comparisons (Fig. 1b, c, Additional file 2: CP_HuD_031 HuD (grade IV ) 80 M 24 Table S2). Almost all probe sets differentially expressed (p < 0.01) in the AD samples had significant or a trend toward differential expression in the same direction in the other two disease groups (Fig. 1c, Additional file 2: after normalizing to 50 ng total RNA input (NuGEN Table S2). In Additional file 4: Table S4 are listed the top Technologies, San Carlos, CA). Gene expression profil - 10 most upregulated and 10 most downregulated genes ing was performed with a customized Human Affym - from the AD vs. Ctrl comparison; 80% of these findings etrix GeneChip microarray (GEO platform GPL 10379) were confirmed by multiple probe sets when available on that included 57,060 probe sets (Affymetrix, Santa Clara, the array. CA). Hybridization (45 °C for 18 h), labeling, and scan- In order to validate these findings with different sub - ning, using Affymetrix ovens, fluidics stations, and jects and gene expression platforms, we compared the scanners, were conducted following the protocols recom- results in whole CP to those obtained by Bergen et al. mended (NuGEN Technologies). All 20 samples passed in laser-dissected CP epithelial cells from control and RNA integrity and Affymetrix quality control metrics. AD subjects [26]. We anticipated that the changes The final sample set contained RNA from 6 Ctrl, 7 AD, reported in CP epithelial cells would also be evident 4 FTD and 3 HuD subjects (Table 1, Additional file 1: in the whole CP samples but to a lesser degree given Table S1). the presence of additional cell types such as stroma and immune cells in the whole tissue samples. Indeed, the Data processing, statistics and annotation 36 genes reported as differentially expressed in AD CP Data were normalized by robust multiarray average epithelium by microarray, and in some cases [17] also (RMA) [27], and each sample was ratioed to the average by quantitative PCR (Bergen et al. Tables 1 and 2 in of the Ctrl samples [28]. Statistical analysis and agglom- [26]), were regulated similarly in AD whole CP tissue in erative clustering were performed using MathWorks our study (r ~ 0.7), but to a lesser magnitude (by ~ 35%, MatLab (Natick, MA). In some statistical analyses, due as indicated by linear regression in Fig. 1d). 34 of the 36 to insufficient power, HuD and FTD data were com - differentially expressed genes reported by Bergen et al. bined into one non-AD disease grouping, as indicated [26] were modulated in the same direction from Ctrl in by: (HuD + FTD). Gene set annotation analysis was per- both studies, with 20 obtaining significance (p < 0.05) in formed by comparing input sets to GeneGo (http://www. the current AD whole CP tissue comparison. Similarly geneg o.com) and Ingenuity (http://www.ingen uity.com) the expression values in whole CP from FTD and HuD pathway sets. Bonferroni-corrected hypergeometric Stopa et al. Fluids Barriers CNS (2018) 15:18 Page 4 of 10 Fig. 1 Significant gene expression differences between Ctrl and diseased CP: a T-test p-value distributions among all probe sets for AD (red), FTD (blue) and HuD (green) vs. Ctrl samples, as well as AD vs. combined FTD plus HuD samples (orange). Gray data points indicate number of significant probe sets expected by chance. b Overlap of probe sets differentially expressed (p < 0.01) between Ctrl and AD (red), Ctrl and FTD (blue) and Ctrl and HuD (green) subjects. c Heatmap of probe sets differentially expressed (p < 0.01) between AD and Ctrl subjects. Probe sets were ordered by agglomerative clustering. Correlation between expression changes in whole CP from AD (d), FTD (e), and HuD (f) to those reported by Bergen et al. [26] in laser-dissected CP epithelial cells from AD subjects. Plotted are the 36 genes reported in Tables 1 and 2 by Bergen et al. [26] that were also represented on the array used in our study. Values are relative to corresponding study Ctrl subjects. Filled circles had p < 0.05 in the corresponding whole CP comparisons. Dotted lines, the provided equation and r values represent linear fit of the data also correlated with those reported for AD CP epithe- Many differences between AD and Ctrl were also lium in reference # [26] (r = 0.8 and 0.6, respectively, observed in HuD vs. FTD (Fig. 1, Additional file 2: Fig. 1e, f ). Table S2). However, there were also some significant dif - In this study, among the 3935 probe sets differen - ferences between AD vs. HuD + FTD, with 902 (1.6%) tially expressed (p < 0.01) in AD compared to Ctrl sub- probe sets significant at p < 0.01 (63% FDR) (Fig. 3). Fig- jects, 2332 were upregulated and 1603 downregulated ure 3a displays the genes up and down-regulated in AD (Fig. 1b, Additional file 2: Table S2). The differentially more than in the combined HuD + FTD group; whereas expressed genes were examined for overlap with ~ 2000 Fig. 3b presents the opposite, i.e., genes regulated more GeneGo and Ingenuity pathways. Ninety-two path- in HuD + FTD than in AD. The 513 probe sets uniquely ways were enriched (Bonferroni corrected p-value, i.e., upregulated in AD: AD vs. Ctrl (p < 0.01) and AD vs. e-value, < 0.01) among the upregulated genes. These HuD + FTD (p < 0.05) were enriched (e < 0.1) predomi- enrichments represented primarily immune-related nately in interleukin and VEGF signaling genes (Addi- pathways, including acute phase response, cytokine and tional file 3: Table S3c). There were 272 probe sets interferon signaling, NFkB, and cell adhesion, as well as uniquely downregulated in AD: AD vs. Ctrl (p < 0.01) growth factor, JAK-STAT and mTOR signaling pathways, and AD vs. HuD + FTD (p < 0.05) but were not signifi - PPAR signaling and protein/nucleic acid salvage path- cantly (e < 0.1) enriched in any queried pathway. The 112 ways (Fig. 2, Additional file 3: Table S3a). Pathway enrich- probe sets uniquely upregulated in HuD + FTD, that is, ment among downregulated genes was less extensive HuD + FTD vs. Ctrl (p < 0.01), and HuD + FTD vs. AD (12 pathways with e < 0.01), including genes involved in (p < 0.05), were enriched (e < 0.1) in cadherin-mediated methionine degradation and protein translation (Fig. 2, cell adhesion (Additional file 3: Table S3d). The 115 probe Additional file 3: Table S3b). sets uniquely downregulated in AD vs. Ctrl (p < 0.01), Stopa et al. Fluids Barriers CNS (2018) 15:18 Page 5 of 10 Fig. 2 Up-regulation of the JAK-STAT and mTOR pathways: Ingenuity pathway maps for a JAK-STAT signaling (transducing extracellular signals to transcriptional responses) and b mTOR signaling (a master regulator for many fundamental cellular repair processes). Genes with AD vs. Ctrl (p < 0.01) are outlined in red, and filled with red or green, indicating the magnitude of increased or decreased expression, respectively, in AD Fig. 3 Expression changes unique to AD, or to the combined HuD + FTD, non-AD ‘disease control’ group: a Heatmap of probe sets differentially expressed between AD and Ctrl subjects (p < 0.01), and altered more relative to the control in the AD group than in the non-AD ‘disease control’ group (AD/Ctrl)/(HuD + FTD/Ctrl) > 1, and AD vs. HuD + FTD, (p < 0.05). Probe sets are ordered by agglomerative clustering. b Heatmap of probe sets differentially expressed between the combined HuD + FTD group and Ctrl subjects (p < 0.01), and altered more relative to the combined HuD + FTD disease control group than in the AD group (HuD + FTD/Ctrl)/(AD/Ctrl) > 1, and HuD + FTD vs. AD, (p < 0.05). Probe sets were ordered by agglomerative clustering. Red (magenta) and green (cyan) indicate the magnitude of increased and decreased expression, respectively downregulated 1.6-, 1.9- and 2.5-fold in AD, FTD and and AD vs. HuD + FTD (p < 0.05), were not significantly HuD, respectively, reaching significance in FTD (respec - (e < 0.1) enriched in assessed biological pathways. tive p values of 0.071, 0.028 and 0.059). Multiple inter- The emphasis here is on gene sets and associated bio - feron signaling genes were upregulated in AD: IFI-TM1 logical pathways. Still, it is instructive to focus on several (p = 0.0008), IFN-AR1 (p = 0.006), IFN-AR2 (p = 0.0007) genes/proteins currently of great interest in CP patho- and IFN-GR2 (p = 0.0002). The complete lists of differ - physiology. Altered tight junction protein claudin-5 in entially-expressed genes, as well as enriched biologi- CP is associated with BCSFB breaching [26], while inter- cal pathways, are provided in Additional file 2: Table S2, feron has a protein-signaling role that couples choroidal- Additional file 3: Table S3, Additional file 4: Table S4. cerebral neuroimmune interactions [13]. Claudin-5 was Stopa et al. Fluids Barriers CNS (2018) 15:18 Page 6 of 10 Discussion samples passing stringent criteria. Moreover, our empha- Comparing gene expression in CP of AD subjects to that sis was on significantly-enriched pathways (affecting of Ctrls and other neurodegenerative diseases reveals multiple genes within a given pathway) rather than spe- important biological functions altered by dementia gen- cific gene targets, with possible individual false discov - eration and progression. The CP as a dynamic interface eries. Any residual blood elements in specimens would between blood, CSF and brain, is able to monitor distor- unlikely explain differences in tissue mRNA among the tions and homeostatically respond, e.g., by the JAK-STAT three disease groups. The somewhat younger Ctrl group pathway as well as cytokine and protein-signaling mol- may be advantageous in avoiding potentially confound- ecules [12, 13]. These homeostatic adjustments impact ing issues with clinically-silent early dementia in an older neural viability. This intimates that CP beneficial adjust - ‘Ctrl’ cohort, otherwise presumed normal. ments, as well as BCSFB malfunctioning, are pertinent We used GeneGo (http://www.geneg o.com) and Inge- to AD progression. The strategic role of CSF to safeguard nuity (http://www.ingen uity.com) sets for pathway analy- brain is manifested by CP upregulation of many genes in sis. In AD compared to Ctrls, this revealed upregulated response to neurodegeneration ([26] and this investiga- inflammation genes: acute phase response, cell adhesion tion); and by its ability to protect basic CSF composition and cytokine, interferon, JAK-STAT signaling (for trans- (e.g., K, pH and vitamin homeostasis) even in advanced lating extracellular signals into transcriptional responses). AD [7]. Nevertheless, the CP in AD incurs structural Notable downregulated pathways were methionine deg- damage [20] and distorted epithelial metabolism and radation and protein translation; both are implicated in transport (e.g., Aβ, cytokine (e.g., TNFα) and methio- AD pathology. Claudin-5 expression was downregulated, nine/homocysteine [24, 29]). The injured epithelium consistent with the enhanced leakiness of the BCSFB likely depends on enhanced mTOR expression to facili- [31] encountered in neurodegenerative diseases [26] and tate cellular repair and/or replacement. Accordingly, the pathophysiology models [29]. Amyloid beta peptide (Aβ) state of CP–CSF viability in ongoing neurodegeneration damages CP tight junctions by activating matrix metal- is a balance between debilitating and restorative events at loproteineases, thereby increasing paracellular permea- the BCSFB [29–31]. bility [32]. The functional significance of such altered CP In this study we have shown numerous transcriptional pathways, for disease outcome, awaits elucidation. alterations in the CP of subjects with neurodegenera- Prominent in AD was upregulated inflammation- tive disease. Given that the BCSFB makes adjustments in related signaling. These inflammation signatures dif - CSF composition, the prolific disease-induced expression fer from cortex-associated microglial infiltration [33, changes in CP fits previous homeostasis modeling [1, 34]. Key marker genes of cortical inflammation-APOE, 30]. Most transcript changes were common to AD, FTD TREM2, TYROBP-did not upregulate in AD CP. Rather, and HuD, while fewer genes were modulated differently acute phase response genes dominated the upregulation: between AD and HuD + FTD. It is instructive to com- multiple cytokine and interferon receptors, JAK-STAT pare the present observations with an earlier transcrip- signaling components, MAPK, NFκB signaling and cell tional investigation of the BCSFB in AD [26]. Whereas adhesion. Cytokines and growth factors in disease-asso- we studied homogenates of entire CP, including epithe- ciated reactions in BCSFB come from brain [35], blood, lium and stroma, Bergen et al. studied single epithelial or CP itself. The CP responds biochemically and tran - cells captured by laser microscopy [26]. Thus, Bergen scriptionally to circulating cytokines, central injury and et al. provided data on epithelium-specific changes in systemic diseases [18, 36, 37]. Localized CP immunoreac- AD (larger-fold changes, see Fig. 1d–f ), while our data- tions (e.g., inflammation-resolving leukocyte trafficking) set also includes potential pathophysiological interac- may benefit brain by sensing ‘injury signals’ flowing from tions between CP stroma and epithelium. Indeed, robust brain to CSF to CP, then feeding back to make homeo- inflammatory responses were not reported by Bergen static neural adjustments [35]. et al. [26], suggesting deductively that the immune-reac- At certain stages of advancing neuroinflammation tive pathophysiology occurs primarily within CP stroma. (caused by brain-residing pro-inflammatory micro - Some limitations of our study include the small num- glial responses to Aβ loads), the CP receives plasma ber of patients in the HuD and FTD groups, and the interferon-γ as a signal to promote homeostatic transport lack of direct confirmation of specific genes by RT-PCR. of anti-inflammatory monocyte-derived macrophages Future studies with a larger N value for HuD and FTD into CSF for resolving parenchymal inflammation will increase the statistical power for disease compari- [12]. Disease-induced disruption of this neuroimmune sons. For post-mortem tissue, RNA stability is challeng- interferon adjustment at the BCSFB [38] could com- ing with autopsy specimens collected at various PMIs; promise the ability of the CSF–brain to thwart AD exac- however, we carefully assessed RNA integrity, using only erbation. The CP competently adapts to AD stress [39] Stopa et al. Fluids Barriers CNS (2018) 15:18 Page 7 of 10 by maintaining an immunosuppressant profile of fac - maintaining endothelial cell fenestration in CP capillaries tors, e.g., VEGF and TGFβ1 in CSF, to help manage brain [49], an important microstructural feature for delivering inflammation after neuronal injury [40]. plasma substances into the choroidal interstitium for epi- Increased expression of LRP-1, a choroidal Aβ trans- thelial processing. porter, agrees with mouse AD modeling [24]. Upregu- Cadherin, on the other hand, was upregulated in FTD lated LRP-1 in the apical membrane expedites Aβ and HuD but not AD. Cadherin is a superfamily of cel- removal from CSF [24]. Augmented reabsorptive clear- lular adhesion molecules (CAM), that maintain tissue ance of Aβ at the BCSFB aids the CNS because cerebral structure and boundaries between cells and organelles. capillaries in AD extrude less Aβ [41]. This compensa - CAM binding also modifies gene expression. Cell–cell tory Aβ removal by CP counters the disabled microves- adhesions mediate specific immune actions [50], of sels [42]. Titers of inflammatory cytokines and choroidal which there is a plethora in CP of FTD and HuD patient proteins, in CSF and blood, present in different degrees specimens. A cadherin family member prominent in in AD [43]. Activated astrocytes and microglia congre- CP is γ-protocadherin (γ-Pcdh), expressed at the apical gate in Aβ plaques [44]. The manner in which CP inflam - membrane [51]. Mutation of γ-Pcdh causes ventricu- matory-signaling molecules modify AD pathogenesis lar collapse. Keep et al. proposed an immune and CSF is heterogeneous. Acute inflammation may beneficially dynamics role for CP γ-Pcdh [52], that co-expresses with promote CSF clearance of affected cells and Aβ aggre - the NaBCN2 Na transporter supporting CSF secretion. gates, protecting neurons. However, persistently-elevated This gene may function in CP ion transport-CSF forma - CP–CSF cytokines and sustained activation of microglia tion by way of apical–microskeletal membrane interac- adversely affect neurons. An effective CP will balance the tions with NaBCN2 that regulate ion trafficking [32]. beneficial vs. detrimental effects of CSF cytokine changes Moreover, Kolmer immune cells, attached to CP apical in AD, FTD and HuD. surface [53], may have an altered function in neurode- Amyloid beta induces cytokine production; and astro- generative diseases when cadherin is upregulated. cytes activated by Aβ, release inflammatory factors that We hypothesize that the downregulated expression sustain Aβ production. Clearly the CP–CSF, using solu- observed in this study reflects failing metabolic pathways ble signals and upregulated cellular adhesion factors, involved in choroid cell and CSF homeostasis. Reduc- appropriately distributes certain T cell phenotypes to tion in methionine-degradation genes is intriguing given CSF [12]; such leukocyte penetration into CSF helps to that excessive homocysteine, a product of methionine control neuroinflammation and Aβ levels in AD brain. metabolism, is a risk factor for AD [54–57]. Methionine The dynamic relationship between pro-inflammatory and loading increases brain homocysteine, Aβ and phospho- anti-inflammatory cytokines in CP–CSF impacts neuro - tau in mouse models [58]. Decreased expression in AD inflammation processes and AD pathology. CP of the methionine-degrading gene may relate to ele- Peroxisome-proliferator-activated receptor (PPAR) vated homocysteine levels in CSF [59]. The impact of signaling genes, including PPARδ and its obligate het- augmented CSF homocysteine on raising brain Aβ and erodimer RXRα, were enriched in AD CP. PPAR/RXRs tau hints that additional methionine gene studies on CP are neuroprotective in AD and Aβ therapies due to anti- transcription factors and metabolism in neurodegenera- inflammatory and endothelial actions [43]. PPAR acti - tive diseases are needed. vation, through endogenous or synthetic ligands, likely We also determined a decreased expression of protein protects CP by increasing antioxidant capacity and translation genes, including multiple eukaryotic transla- improving energy supply; this maintains fuel for the Na tion initiation factors (EIF genes) and ribosomal proteins. pump [45] and CSF secretion [46], and increases expres- CP has a major role in producing and secreting CSF sion of Aβ transporters [47]. The novel GFT1803 agent proteins, e.g., transthyretin that stabilizes Aβ confor- (a pan-PPAR agonist that activates all 3 PPAR isoforms) mation. In AD there is decreased choroidal synthesis of attenuates Aβ loading-induced damage and neuroinflam - transthyretin [24], lowering its CSF concentration [60]. mation [48]. PPAR thus deserves attention as a potential Moreover, the heat stress glucose regulatory proteins 78 pathway for restoring CP–CSF integrity in AD in order to and 94 in human AD CP are diminished [39], implicating counter neurodegeneration. suboptimal glucose or calcium homeostasis. Altered heat Significant expression differences were also observed stress proteins at the AD BCSFB deserve examination for between AD and FTD + HuD. The VEGF signaling path - impact on cerebral metabolism. way (including VEGFA and VEGF receptors FLT1 and Expression of mTOR associates with controlling cell FLT4) displayed significant upregulation in AD but not in growth and proliferation [61], possibly a factor as dam- FTD or HuD. This agrees with our previous findings of aged choroid epithelial cells need replacement. Our increased VEGF within AD CP [1]. VEGF is required for finding of increased fatty acid oxidation and upstream Stopa et al. Fluids Barriers CNS (2018) 15:18 Page 8 of 10 mTOR signaling (Fig. 2), with juxtaposed downregu- Additional files lated protein translation, fits existing concepts sug - gesting altered energy metabolism in AD onset and Additional file 1: Table S1. Sample Annotations and Patient Demograph- progression. While increased PPAR activity down- ics: ‘QC passed’ indicates samples passing both RNA and Affymetrix quality stream of mTOR fits the compensatory adaptation control, and used for analysis. APOE; genotype data consist of combina- to retain CP resiliency, there is a disconnect between tions of the ε2, ε3 and ε4 alleles, with ε4 carrying the highest risk for brain injury; Bioanalyzer (BA); RNA Integrity (RIN). upregulated mTOR and the downregulated protein Additional file 2: Table S2. T-test results for choroid plexus RNA from 6 translation machinery typically induced by mTOR. control, 7 Alzheimer’s disease, 4 FTD and 3HUD subjects: T-test p-values This suggests a break in normal mTOR signaling (see and expression differences (Log Disease/Ctrl) for each disease type are Fig. 2) that could undermine CP function or resiliency provided for all 5760 Affymetrix probesets measured. Values for the AD vs. HuD + FTD subject comparison are also provided. when challenged with neurodegeneration. This is sig - Additional file 3: Table S3. Geneset Annotations: Worksheets contain nificant because of CP’s pivotal role in providing brain pathways enriched among genes upregulated in AD vs. Ctrl (S3a); down- with supportive factors and immune cells that migrate regulated in AD vs. Ctrl (S3b); upregulated in AD but not in HuD + FTD vs. across BCSFB into CSF–brain. Studies need to assess Ctrl (S3c); and upregulated in HuD + FTD but not AD vs. Ctrl (S3d). Hyper- geometric p-values (p-value), Bonferroni-corrected p-values (E-value), the role of the dynamic CP transcriptome in providing overlaps and input and background set sizes are provided. resiliency to the BCSFB, in order to retain CSF homeo- Additional file 4: Table S4. The top 10 most upregulated and top 10 static reserve for staving off neurodegeneration. most downregulated genes in the AD vs. Ctrl comparison, with p < 0.01. Multiple probe set data, where available, are included in the comparisons. Conclusions The AD transcript findings reported herein for bulk CP Abbreviations tissue compare favorably with and expand prior analy- Aβ: amyloid beta; AD: Alzheimer’s disease; APOE: apolipoprotein; BCSFB: blood–CSF barrier; CP: choroid plexus; CSF: cerebrospinal; EIF: eukaryotic trans- sis in laser-captured epithelial cells [26]. Such concur- lation initiation factors; FDR: false discovery rate; FTD: frontotemporal demen- rence is remarkable given the different tissue sampling, tia; HuD: Huntington’s disease; JAK-STAT : Janus kinase/signal transducers and measurement platforms and patient cohorts. Highlights activators of transcription; LRP1: low density lipoprotein receptor-related protein 1; mTOR: mechanistic target of rapamycin; PMI: post-mortem interval; of our investigation include upregulated genes linked to PPAR: peroxisome-proliferator-activate receptor; RAGE: receptor for advanced inflammation and interferon neuroimmune homeostasis, glycation end product; TGFβ: transforming growth factor beta; VEGF: vascular as well as to JAK-STAT and mTOR; and downregulated endothelial growth factor. genes for methionine degradation, protein translation Authors’ contributions and claudin-5 (tight junction). CP is a complex homeo- ES conceived the original research design, wrote/edited a significant part static tissue. The BCSFB undergoes deleterious, but of the paper, and coordinated the manuscript input from various authors. KT conducted the bioinformatics/statistical analyses, constructed figures/ sometimes functional and adaptive, changes in dementia- tables, and wrote/edited part of the manuscript. MM processed the choroid related pathophysiology. The enriched JAK-STAT and plexus specimens, contributed to research design, and organized datasets for mTOR pathways (Fig. 2), respectively, are likely instru- uploading to the Gene Expression Omnibus (GEO). EN, AP, EF, DS, LC, LP, AV, AB, JD, TT, BE, and GS participated in tissue collection/processing, discussed mental in promoting adaptive transcriptional responses aspects of experimental design/execution, or helped with manuscript prepa- and epithelial repair/replacement when CP is harmed by ration. CJ participated in the project planning, wrote/edited a large part of the injuries associating with neurodegeneration. Analyzing paper, and integrated manuscript input from all authors. All authors read and approved the final manuscript. biological pathway mechanisms expedites specific phar - macologic targeting. Author details Future transcriptome work with larger cohorts should Departments of Neurosurgery and Pathology (Neuropathology Division), Rhode Island Hospital, The Warren Alpert Medical School, Brown University, delineate gene expression by demographic endpoints, Providence, RI, USA. Genetics and Pharmacogenomics, Merck & Co., Inc., West Braak staging, Aβ plaque score, disease duration, ApoE 3 4 Point, PA, USA. United Neuroscience, Dublin, Ireland. Department of Sur- genotype, co-morbidity, and other disease character- gery, University of California San Diego Medical Center, Hillcrest, 212 Dickinson Street, San Diego, CA, USA. istics. The transcriptome distinctions here precisely describe CP–CSF function in, and response to, certain Acknowledgements neuropathologies: AD vs. FTD vs. HuD. This categorical The authors would like to thank the families of patients with AD, referred from the Department of Neurology at Rhode Island Hospital, for donating patient approach provides crucial knowledge on the BCSFB role brains to the Brown University Brain Tissue for Neurodegenerative Disorders in pathogenesis; and hopefully should improve prophy- Resource Center. laxis of various neural diseases. The goal: To identify Competing interests exact CP targets to exploit when implementing pharma- The authors declare that they have no competing interests. cologic/genetic therapies to alleviate CSF–brain meta- bolic distortions in dementia. Stopa et al. Fluids Barriers CNS (2018) 15:18 Page 9 of 10 Availability of data and materials 13. Schwartz M, Deczkowska A. Neurological disease as a failure of brain- The datasets analyzed during the current study are available under the Gene immune crosstalk: the multiple faces of neuroinflammation. Trends Expression Omnibus (GEO) Accession GSE110226 at the National Center for Immunol. 2016;37(10):668–79. Biotechnology Information (NCBI) at the National Library of Medicine, National 14. Spector R, Johanson CE. Choroid plexus failure in the Kearns-Sayre syn- Institutes of Health. drome. Cerebrospinal Fluid Res. 2010;7(1):14. 15. Vercellino M, Votta B, Condello C, Piacentino C, Romagnolo A, Merola Consent for publication A, Capello E, Mancardi GL, Mutani R, Giordana MT, et al. Involvement of All authors agree with publication of this manuscript. the choroid plexus in multiple sclerosis autoimmune inflammation: a neuropathological study. J Neuroimmunol. 2008;199(1–2):133–41. Ethics approval and consent to participate 16. Millward JM, Ariza de Schellenberger A, Berndt D, Hanke-Vela L, Schel- This research was approved by the Institutional Review Board for Clinical lenberger E, Waiczies S, Taupitz M, Kobayashi Y, Wagner S, Infante-Duarte Research at Lifespan, Rhode Island Hospital, Providence, RI. C. Application of europium-doped very small iron oxide nanoparticles to visualize neuroinflammation with MRI and fluorescence microscopy. Funding Neuroscience. 2017. https ://doi.org/10.1016/j.neuro scien ce.2017.12.014. This study was supported by funds provided by Merck & Co. (for CP tissue 17. Kim S, Hwang Y, Lee D, Webster MJ. Transcriptome sequencing of the transcript analyses and bioinformatical/statistical work), and by the Division choroid plexus in schizophrenia. Transl Psychiatry. 2016;6(11):e964. of Neuropathology at Rhode Island Hospital (for CP tissue storage/processing 18. Marques F, Sousa JC, Coppola G, Falcao AM, Rodrigues AJ, Geschwind DH, and manuscript costs). 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Fluids and Barriers of the CNS – Springer Journals
Published: May 31, 2018