Astrocytes and Microglia Both Help and Harm the Blood-Brain Barrier in Aging

The blood-brain barrier wraps blood vessels where they pass through the central nervous system, controlling the passage of cells and molecules into and out of the brain. The blood-brain barrier becomes disrupted with age, allowing unwanted molecules into the brain, where they can spur chronic inflammation and dysfunction contributing to neurodegeneration. Researchers here investigate the response of astrocytes and microglia, supporting cells of the brain, to the age-related leakage of the blood-brain barrier, in search of points of intervention.

Blood-brain barrier (BBB) breakdown facilitates entry into the brain of neurotoxic blood-derived products and pathogens and has been linked to inflammatory and immune responses that can induce neuronal injury, synaptic dysfunction, and loss of neuronal connectivity. BBB disruption also facilitates leukocyte infiltration, which leads to glial cell death, axonal damage, lesion development, and therefore cerebrovascular dysfunction results in memory impairment, acceleration of neurovascular damage, and exacerbation of the progression of neuropathology in the central nervous system (CNS). Thus, critical demand exists for new therapies that minimize peripheral immune factors and limit the infiltration of peripheral immune cells into the brain.

The neurovascular unit, which comprises brain endothelial cells, pericytes, astrocytes, and microglia, primarily confers the low paracellular permeability of the BBB. The tight cell-to-cell contacts that these cell types establish with each other restrict the entry of red blood cells, leukocytes, and plasma components into the brain parenchyma and ensure the export of potentially neurotoxic molecules from the brain to the blood. The site of the anatomical BBB is composed of a continuous monolayer of endothelial cells that are connected by tight junctions (TJs) and adherens junctions. The interactions among the endothelial cells, pericytes, and glial cells are crucial for the formation and maintenance of the highly regulated CNS internal milieu.

Astrocytes play a dual role in limiting the entry of peripheral substances into the CNS: permeability factors secreted by reactive astrocytes open the BBB by disrupting endothelial TJs, but reactive astrocytes also perform a protective function by upregulating classical TJ proteins and using TJ proteins to corral activated T lymphocytes into distinct clusters. Microglia have also recently been shown to contribute to BBB induction, and studies have indicated that microglia also play a dual role in BBB repair. Initially, microglia maintain BBB integrity by expressing the TJ protein Claudin-5 and establishing physical contacts with endothelial cells, but during persistent inflammation, microglia engulf astrocytic endfeet and endothelial cells and impair BBB function.

Here, we investigated the transcriptional changes that occur in microglia and astrocytes by performing RNA sequencing on samples from five time points across the BBB permeability change during aging in mice. We report that whereas microglia are characterized by marked gene-level alterations related to negative regulation of protein phosphorylation and phagocytic vesicles, astrocytes show activation of enzyme- or peptidase-inhibitor signaling after detectable changes in BBB permeability. We also identify several genes enriched in these pathways that are notably altered after BBB breakdown. Our data reveal that microglia and astrocytes play an active role in maintaining BBB stabilization and corralling infiltrating cells, and thus might potentially function in ameliorating the lesions and neurologic disabilities in CNS diseases.



Astrocytes and Microglia Both Help and Harm the Blood-Brain Barrier in Aging