Microglia directly associate with pericytes in the central nervous system

Abstract

Cerebral blood flow (CBF) is important for the maintenance of brain function and its dysregulation has been implicated in Alzheimer's disease (AD). Microglia associations with capillaries suggest they may play a role in the regulation of CBF or the bloodbrain-barrier (BBB). We explored the relationship between microglia and pericytes, a vessel-resident cell type that has a major role in the control of CBF and maintenance of the BBB, discovering a spatially distinct subset of microglia that closely associate with pericytes. We termed these pericyte-associated microglia (PEM). PEM are present throughout the brain and spinal cord in NG2DsRed  CX 3 CR1 +/GFP mice, and in the human frontal cortex. Using in vivo two-photon microscopy, we found microglia residing adjacent to pericytes at all levels of the capillary tree and found they can maintain their position for at least 28 days. PEM can associate with pericytes lacking astroglial endfeet coverage and capillary vessel width is increased beneath pericytes with or without an associated PEM, but capillary width decreases if a pericyte loses a PEM. Deletion of the microglia fractalkine receptor (CX 3 CR1) did not disrupt the association between pericytes and PEM. Finally, we found the proportion of microglia that are PEM declines in the superior frontal gyrus in AD. In summary, we identify microglia that specifically associate with pericytes and find these are reduced in number in AD, which may be a novel mechanism contributing to vascular dysfunction in neurodegenerative diseases.

Pericyte ablation causes hypoactivity and reactive gliosis in adult mice

“…Consistent with our previous report (Morris et al, 2023a), only ~7% of OPCs were labelled with DsRed across all brain regions analysed (Supplementary Figure 3A-C). OPCs that were DsRed + also had a significantly less intense nuclear DsRed signal compared to pericytes (Supplementary Figure 3D; p < 0.0001).…”

Ultrastructure of the brain waste-clearance pathway

“…A recent study discovered that microglia directly associate with pericytes(Morris et al 2023). Utilizing the MICrONS dataset, the authors suggested a direct contact between microglial and pericyte cell bodies through an astrocytic endfoot fenestration.…”

Plaque vicinity as a hotspot of microglial turnover in a mouse model of Alzheimer's disease

“…The recent literature data point to a close association and interaction between brain vasculature and microglia. Indeed, under steady-state conditions, 20%-30% of microglia in the adult brain are associated with blood vessels (Bisht et al, Mondo et al, 2020), and their processes are in close contact with different components of the neurovascular unit, including endothelial cells, pericytes and astrocytes (Császár et al, 2022;Morris et al, 2023). Interactions between microglial processes and vascular structures are important for the maintenance of optimal capillary diameter and cerebrovascular blood flow under basal conditions as well as during sensory stimulation-induced functional hyperemia, and the absence of microglia or blockade of microglial P2Y 12 receptors substantially impairs neurovascular coupling (Bisht et al, 2021;Császár et al, 2022).…”

“…At the onset of inflammation and before any detectable change in permeability of the blood-brain barrier, this migration toward and accumulation around cerebral vessels likely served to protect blood-brain barrier integrity (Haruwaka et al, 2019). This integrity seems to be impaired in post-mortem AD brain tissue with microglia showing a reduced association with capillaries and pericytes, which might contribute to vascular pathology (Morris et al, 2023).…”

“…In the healthy brain, individual microglial cells occupy nonoverlapping territories (so-called spatial domains), which they continuously scan for danger signals with their branched and highly motile processes (Davalos et al, 2005;Nimmerjahn et al, 2005). By doing so, they frequently interact with other spatial domain inhabitants like neurons, astrocytes, endothelial, and smooth muscle cells of blood vessels as well as pericytes (Császár et al, 2022;Morris et al, 2023;Nimmerjahn et al, 2005;Tremblay et al, 2010;Wake et al, 2009). In addition to process movement, brain patrolling may also involve a movement of cell somata (somatic translocation).…”