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

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

doi:10.1186/s12987-018-0102-9

Cited by 92 publications

(83 citation statements)

References 58 publications

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“…Future studies should explore the involvement of granulocytes in CP-mediated MS pathology, including whether their release of reactive oxygen species is related to the hypoxia-like responses observed. Previous transcriptomic studies of the CP from other neurological diseases detected alterations in immune-related pathways [34,70]. Moreover, our recent study indicated that CD8+ T cells are more abundant in progressive MS CP than in control, which we could not detect in the present work.…”

Section: Discussioncontrasting

confidence: 84%

“…Higher PAI-1 concentrations have been previously detected in the CSF of MS patients compared to that in controls [1]. Moreover, higher SERPINE1 expression was detected in the CP of Alzheimer's and Huntington's disease and frontotemporal dementia patients relative to controls [70]. Our findings suggest that in the most severe cases of progressive MS the CP secretes higher levels of PAI-1 into the CSF, where it can travel into lesion-prone periventricular areas in an attempt to promote neuroprotection.…”

Section: Discussionmentioning

confidence: 80%

“…To our knowledge, this is the first transcriptomic characterization of the progressive MS CP in a human setting. RNA-seq of the CP in other neurological diseases such as frontotemporal dementia, Alzheimer's and Huntington's disease [70], or schizophrenia [34] revealed alterations in the barrier or immune homeostatic properties of the CP. In progressive MS, we found predominantly alterations related to hypoxia but also secretion and neuroprotection, possibly reflecting the particular etiology of MS.…”

Section: Discussionmentioning

confidence: 99%

“…In the past years, there is increasing evidence of the involvement of the CP in a variety of disorders such as ageing [3,16,83], Alzheimer's disease [30,70], frontotemporal dementia [70], schizophrenia [34], Huntington's disease [70] and cerebral ischemia [66]. In MS, the presence of periventricular lesions and the increased numbers of immune cells in the CSF [11] suggest an involvement of the CP in regulating pathology.…”

Section: Introductionmentioning

confidence: 99%

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Altered secretory and neuroprotective function of the choroid plexus in progressive multiple sclerosis

Rodríguez‐Lorenzo

Francisco

Vos

et al. 2020

acta neuropathol commun

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The choroid plexus (CP) is a key regulator of the central nervous system (CNS) homeostasis through its secretory, immunological and barrier properties. Accumulating evidence suggests that the CP plays a pivotal role in the pathogenesis of multiple sclerosis (MS), but the underlying mechanisms remain largely elusive. To get a comprehensive view on the role of the CP in MS, we studied transcriptomic alterations of the human CP in progressive MS and non-neurological disease controls using RNA sequencing. We identified 17 genes with significantly higher expression in progressive MS patients relative to that in controls. Among them is the newly described long non-coding RNA HIF1A-AS3. Next to that, we uncovered disease-affected pathways related to hypoxia, secretion and neuroprotection, while only subtle immunological and no barrier alterations were observed. In an ex vivo CP explant model, a subset of the upregulated genes responded in a similar way to hypoxic conditions. Our results suggest a deregulation of the Hypoxia-Inducible Factor (HIF)-1 pathway in progressive MS CP. Importantly, cerebrospinal fluid levels of the hypoxia-responsive secreted peptide PAI-1 were higher in MS patients with high disability relative to those with low disability. These findings provide for the first time a complete overview of the CP transcriptome in health and disease, and suggest that the CP environment becomes hypoxic in progressive MS patients, highlighting the altered secretory and neuroprotective properties of the CP under neuropathological conditions. Together, these findings provide novel insights to target the CP and promote the secretion of neuroprotective factors into the CNS of progressive MS patients.

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Section: Discussioncontrasting

confidence: 84%

Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Altered secretory and neuroprotective function of the choroid plexus in progressive multiple sclerosis

Rodríguez‐Lorenzo

Francisco

Vos

et al. 2020

acta neuropathol commun

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“…Analysis of post mortem samples of patients with Huntington's disease revealed that cadherin was upregulated while claudin-5 was down-regulated implicating them in regulating the number of KC. Moreover, several neuroimmune-modulating interferons were significantly enriched [258]. Transplanted encapsulated CP has been shown to have a neuroprotective effect in Huntington's disease [259].…”

Section: Huntington's Diseasementioning

confidence: 99%

Choroid plexus and the blood–cerebrospinal fluid barrier in disease

Solar

Zamani

Kubíčková

et al. 2020

Fluids Barriers CNS

212

142

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The choroid plexus (CP) forming the blood-cerebrospinal fluid (B-CSF) barrier is among the least studied structures of the central nervous system (CNS) despite its clinical importance. The CP is an epithelio-endothelial convolute comprising a highly vascularized stroma with fenestrated capillaries and a continuous lining of epithelial cells joined by apical tight junctions (TJs) that are crucial in forming the B-CSF barrier. Integrity of the CP is critical for maintaining brain homeostasis and B-CSF barrier permeability. Recent experimental and clinical research has uncovered the significance of the CP in the pathophysiology of various diseases affecting the CNS. The CP is involved in penetration of various pathogens into the CNS, as well as the development of neurodegenerative (e.g., Alzheimer´s disease) and autoimmune diseases (e.g., multiple sclerosis). Moreover, the CP was shown to be important for restoring brain homeostasis following stroke and trauma. In addition, new diagnostic methods and treatment of CP papilloma and carcinoma have recently been developed. This review describes and summarizes the current state of knowledge with regard to the roles of the CP and B-CSF barrier in the pathophysiology of various types of CNS diseases and sets up the foundation for further avenues of research. Publisher's NoteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Pathogenesis of Alzheimer's disease: Involvement of the choroid plexus

Čarná

Onyango

Katina

et al. 2023

Alzheimer's & Dementia

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The choroid plexus (ChP) produces and is bathed in the cerebrospinal fluid (CSF), which in aging and Alzheimer's disease (AD) shows extensive proteomic alterations including evidence of inflammation. Considering inflammation hampers functions of the involved tissues, the CSF abnormalities reported in these conditions are suggestive of ChP injury. Indeed, several studies document ChP damage in aging and AD, which nevertheless remains to be systematically characterized. We here report that the changes elicited in the CSF by AD are consistent with a perturbed aging process and accompanied by aberrant accumulation of inflammatory signals and metabolically active proteins in the ChP. Magnetic resonance imaging (MRI) imaging shows that these molecular aberrancies correspond to significant remodeling of ChP in AD, which correlates with aging and cognitive decline. Collectively, our preliminary post‐mortem and in vivo findings reveal a repertoire of ChP pathologies indicative of its dysfunction and involvement in the pathogenesis of AD.Highlights Cerebrospinal fluid changes associated with aging are perturbed in Alzheimer's disease Paradoxically, in Alzheimer's disease, the choroid plexus exhibits increased cytokine levels without evidence of inflammatory activation or infiltrates In Alzheimer's disease, increased choroid plexus volumes correlate with age and cognitive performance

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

Cited by 92 publications

References 58 publications

Altered secretory and neuroprotective function of the choroid plexus in progressive multiple sclerosis

Altered secretory and neuroprotective function of the choroid plexus in progressive multiple sclerosis

Choroid plexus and the blood–cerebrospinal fluid barrier in disease

Pathogenesis of Alzheimer's disease: Involvement of the choroid plexus

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