Amyloid β Oligomers Disrupt Blood–CSF Barrier Integrity by Activating Matrix Metalloproteinases

Abstract

The blood-CSF barrier (BCSFB) consists of a monolayer of choroid plexus epithelial (CPE) cells that maintain CNS homeostasis by producing CSF and restricting the passage of undesirable molecules and pathogens into the brain. Alzheimer's disease is the most common progressive neurodegenerative disorder and is characterized by the presence of amyloid ␤ (A␤) plaques and neurofibrillary tangles in the brain. Recent research shows that Alzheimer's disease is associated with morphological changes in CPE cells and compromised production of CSF. Here, we studied the direct effects of A␤ on the functionality of the BCSFB. Intracerebroventricular injection of A␤1-42 oligomers into the cerebral ventricles of mice, a validated Alzheimer's disease model, caused induction of a cascade of detrimental events, including increased inflammatory gene expression in CPE cells and increased levels of proinflammatory cytokines and chemokines in the CSF. It also rapidly affected CPE cell morphology and tight junction protein levels. These changes were associated with loss of BCSFB integrity, as shown by an increase in BCSFB leakage. A␤1-42 oligomers also increased matrix metalloproteinase (MMP) gene expression in the CPE and its activity in CSF. Interestingly, BCSFB disruption induced by A␤1-42 oligomers did not occur in the presence of a broad-spectrum MMP inhibitor or in MMP3-deficient mice. These data provide evidence that MMPs are essential for the BCSFB leakage induced by A␤1-42 oligomers. Our results reveal that Alzheimer's disease-associated soluble A␤1-42 oligomers induce BCSFB dysfunction and suggest MMPs as a possible therapeutic target.

Lymphatics in Neurological Disorders: A Neuro-Lympho-Vascular Component of Multiple Sclerosis and Alzheimer’s Disease?

“…Under healthy conditions, however, the blood-CSF barrier (BCSFB) formed by the choroid plexus epithelial cells restricts immune-cell entry into the CSF and the brain parenchyma (Baruch and Schwartz, 2013; Engelhardt et al, 2001; Hasegawa-Ishii et al, 2013). AD patients exhibit major alterations in choroid plexus structure and morphology, as well as in epithelial cell function, attributable mainly to the increase in toxic Aβ peptides (Brkic et al, 2015; Johanson et al, 2004; Vargas et al, 2010). In addition, the ability of epithelial cells to express the transporters that participate in Aβ efflux, as well as to secrete Aβ-scavenging proteins into the CSF and their corresponding receptors, decreases with age and is compromised in different in-vitro and in-vivo models of AD (Antequera et al, 2009; Crossgrove et al, 2005; Zlokovic et al, 1996).…”

MMP-3 Deficiency Alleviates Endotoxin-Induced Acute Inflammation in the Posterior Eye Segment

“…Several reports describe that matrix metalloproteinases (MMPs), i.e., Zn 2+ -dependent endopeptidases that cleave both matrix and non-matrix proteins, are able to degrade basal lamina components and tight junction proteins at the blood–brain barrier (BBB), blood–cerebrospinal fluid barrier (BCSFB) and blood–spinal cord barrier (BSCB), thereby contributing to blood–central nervous system (CNS) barrier disruption and neuroinflammation [11,12,13,14,15,16,17,18,19]. Of note, it is known that the endothelial cells of the BBB/BSCB and the choroid plexus epithelial cells (CPE) that form the BCSFB show similarities with, respectively, the endothelial cells of the inner BRB and the RPE cells of the outer BRB [20].…”

“…In the brain, MMP expression is known to be upregulated by cytokines but also by the bacterial endotoxin LPS. In addition, increased MMP-3 levels have been reported during neuroinflammatory processes [11,14,21,22,23,24,25,26]. Indeed, the MMP-3 gene ( Mmp3 ) promoter contains binding sites for activator protein 1 (AP-1) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), which can both be activated by various inflammatory cytokines [27,28,29,30].…”

Pramlintide: The Effects of a Single Drug Injection on Blood Phosphatidylcholine Profile for Alzheimer’s Disease

“…This study further demonstrated that a combination of mobilized direct AD biomarkers from the brain into blood [10] and an analysis of signature PC levels in the pramlintide challenge test may be a valuable diagnostic test for AD (Figure 5). The existence of BBB and blood-CSF barrier (BCSFB) prevent brain-originating AD biomarkers in the blood from accurately reflecting brain pathology [24, 25] and cause challenges to develop blood diagnostic tests for AD. For example, although plasma Aβ levels are significantly different between AD and controls when a large sample size is used [26, 27], the sensitivity and specificity of these differences are too low to be useful as AD diagnostics [28] [29, 30].…”