Ultrastructural Remodeling of the Blood–Brain Barrier and Neurovascular Unit by Lipopolysaccharide-Induced Neuroinflammation

Abstract

The blood–brain barrier (BBB) is an interface primarily comprised of brain endothelial cells (BECs), separating the central nervous system (CNS) from the systemic circulation while carefully regulating the transport of molecules and inflammatory cells, and maintaining the required steady-state environment. Inflammation modulates many BBB functions, but the ultrastructural cytoarchitectural changes of the BBB with inflammation are understudied. Inflammation was induced in male 8–10-week-old CD-1 mice with intraperitoneal lipopolysaccharide (LPS), using a regimen (3 mg/kg at 0, 6, and 24 h) that caused robust BBB disruption but had minimal lethality at the study timepoint of 28 h. Perfusion-fixed brains were collected and the frontal cortical layer III regions were analyzed using a transmission electron microscopy (TEM). The LPS-treated mice had pronounced ultrastructural remodeling changes in BECs that included plasma membrane ruffling, increased numbers of extracellular microvesicles, small exosome formation, aberrant BEC mitochondria, increased BEC transcytosis, while tight junctions appeared to be unaltered. Aberrant pericytes were contracted with rounded nuclei and a loss of their elongated cytoplasmic processes. Surveilling microglial cells were attracted to the neurovascular unit (NVU) of BECs, and astrocyte detachment and separation were associated with the formation of a perivascular space and pericapillary edema. The LPS treatment resulted in numerous ultrastructural aberrant remodeling changes to the neurovascular unit’s BECs, microglia, pericytes, and astrocytes. In summary, a disturbance of the NVU morphology is a consequence of LPS treatment.

Endothelial deletion of EPH receptor A4 alters single-cell profile and Tie2/Akap12 signaling to preserve blood–brain barrier integrity

“…S2 L and M ). Additional ultrastructural analysis using TEM further demonstrates that iKO perilesional microvascular display reduced numbers of macropinocytic vesicles (125 to 300 nm), predominant mediators of BBB disruption through increased transcytosis of plasma ( 23 , 24 ), at 1 dpi ( Fig. 3 I , K , and L ) compared to iWT ( Fig.…”

Microglia drive diurnal variation in susceptibility to inflammatory blood-brain barrier breakdown

“…Previous TEM studies have also found that LPS induces luminal plasma membrane ruffling, a mechanism of non-receptor mediated pinocytosis used by bacteria and viruses to increase infection of epithelial cells (20,42,43). We found a significant increase in severe luminal irregularity in LPS treated mice at ZT13 only (Figure 3A, D).…”

Antibody Assay and Anti-Inflammatory Function Evaluation of Therapeutic Potential of Different Intravenous Immunoglobulins for Alzheimer’s Disease

“…Intraperitoneal LPS in mice has been shown to induce neuroinflammation, which is characterized by the activation of microglia and astrocytes in the brain [ 19 , 20 ]. Given that the hippocampus is an important organ involved in learning and memory storage in the central nervous system, this study focused on the protective effects of IVIG on the brain and hippocampus.…”