| Autor: |
Morris, Gary P, Foster, Catherine G, Courtney, Jo‐Maree, Collins, Jessica M, Cashion, Jake M, Brown, Lachlan S, Howells, David W, Deluca, Gabriele C, Canty, Alison J, King, Anna E, Ziebell, Jenna M, Sutherland, Brad A |
| Zdroj: |
Alzheimer's & Dementia: The Journal of the Alzheimer's Association; Dec2023 Supplement 13, Vol. 19, p1-1, 1p |
| Abstrakt: |
Background: The majority of individuals with Alzheimer's disease (AD) exhibit vascular damage in the brain including reduced cerebral blood flow (CBF) and blood‐brain‐barrier (BBB) breakdown. Growing evidence suggests pericytes, a vessel‐residing cell able to modulate CBF and BBB integrity, are a major contributor to vascular dysfunction in AD. The close spatial relationship between microglia and capillaries led us to explore the hypothesis that microglia and pericytes functionally interact to influence vessel function in the healthy brain and that this interaction may become pathological in AD. Methods: We first characterized the spatial and functional relationship between microglia, capillaries and pericytes in the healthy central nervous system (CNS) in fixed tissue and using in vivo two‐photon microscopy through cranial windows in adult NG2DsRed x CX3CR1+/GFP mice. We then assessed the spatial relationship between microglia, capillaries and pericytes in the human superior frontal gyrus (SFG) of 12 control and 11 AD cases. Results: We discovered a subset of microglia dynamically interacting with pericytes in the healthy CNS, which we termed pericyte‐associated microglia (PEM). PEM are present throughout the capillary tree, often maintain their position for at least 28 days and frequently were found to associate with pericytes lacking astroglial endfeet coverage. The loss of PEM alters capillary width beneath pericytes, but deletion of the microglial fractalkine receptor (CX3CR1), which regulates the recruitment of microglia to sites of neuroinflammation, does not reduce the proportion of microglia that are PEM. In AD, we found the proportion of microglia associated with capillaries and pericytes declines in the superior frontal gyrus (SFG) and that this decline is exacerbated by the APOE ε3/ε4 genotype. This reduction occurs despite an overall increase in pericyte numbers in AD cases. Conclusion: We identify microglia specifically associating with pericytes in the healthy CNS and find these associations are reduced in AD. The changing relationship between microglia, capillaries and pericytes may be a novel mechanism contributing to vascular dysfunction in AD. [ABSTRACT FROM AUTHOR] |
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