Global alterations to the choroid plexus blood-CSF barrier in amyotrophic lateral sclerosis

J. Saul, J. Saul, E. Hutchins, R. Reiman, M. Saul, L. W. Ostrow, B. T. Harris, K. Van Keuren-Jensen, R. Bowser, R. Bowser, N. Bakkar, N. Bakkar

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

The choroid plexus (CP) is a highly vascularized structure located in the ventricles that forms the blood-CSF barrier (BCSFB) and separates the blood from the cerebrospinal fluid (CSF). In addition to its role as a physical barrier, the CP functions in CSF secretion, transport of nutrients into the central nervous system (CNS) and a gated point of entry of circulating immune cells into the CNS. Aging and neurodegeneration have been reported to affect CP morphology and function and increase protein leakage from blood to the CSF. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with both upper and lower motor neuron loss, as well as altered proteomic and metabolomic signatures in the CSF. The role of the BCSFB and the CP in ALS is unknown. Here we describe a transcriptomic and ultrastructural analysis of BCSFB and CP alterations in human postmortem tissues from ALS and non-neurologic disease controls. ALS-CP exhibited widespread disruptions in tight junctional components of the CP epithelial layer and vascular integrity. In addition, we detected loss of pericytes around ALS blood vessels, accompanied by activation of platelet aggregation markers vWF and Fibrinogen, reminiscent of vascular injury. To investigate the immune component of ALS-CP, we conducted a comprehensive analysis of cytokines and chemokine panels in CP lysates and found a significant down-regulation of M-CSF and V-CAM1 in ALS, as well as up-regulation of VEGF-A protein. This phenotype was accompanied by an infiltration of MERTK positive macrophages into the parenchyma of the ALS-CP when compared to controls. Taken together, we demonstrate widespread structural and functional disruptions of the BCSFB in human ALS increasing our understanding of the disease pathology and identifying potential new targets for ALS therapeutic development.

Original languageEnglish (US)
JournalActa Neuropathologica Communications
Volume8
Issue number1
DOIs
StatePublished - Jun 26 2020

Keywords

  • ALS
  • Blood-CSF barrier
  • Choroid plexus
  • RNA sequencing
  • Tight junctions

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Fingerprint

Dive into the research topics of 'Global alterations to the choroid plexus blood-CSF barrier in amyotrophic lateral sclerosis'. Together they form a unique fingerprint.

Cite this