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. Author manuscript; available in PMC: 2019 Nov 13.
Published in final edited form as: Nat Med. 2019 May 13;25(6):988–1000. doi: 10.1038/s41591-019-0440-4

Extended Data Figure 10. Aged blood inhibits hippocampal NPC activity and activates microglia through VCAM1 at the blood-brain barrier (BBB).

Extended Data Figure 10

In young healthy mice, neurovascular homeostasis is maintained with low expression levels of systemic soluble VCAM1 (sVCAM1) and BBB-specific VCAM1, active neurogenesis with neural stem cells (NSCs) differentiating into NPCs (NPCs), immature neurons and mature neurons, and nonreactive microglia in a low inflammation environment. During aging or exposure to aged plasma, we propose:

1) Inflammatory factors in aged plasma (IL-1β, TNF-α, among others) induce arterial and venous BEC activation and upregulation of VCAM1 through their cytokine receptors Tnfrsf1a and Il1r1.

2) Venous VCAM1 facilitates tethering, but not transmigration, of leukocytes which sustain BEC inflammation.

3) Inflamed and activated venous and arterial VCAM1+ brain endothelium relay (unknown) signals to the parenchyma leading to a loss of homeostasis, decline in NPC activity and chronic activation of microglia.

4) anti-VCAM1 mAb protects young brains from the detrimental effects of aged plasma by reducing BEC-mediated inflammation.

5) anti-VCAM1 mAb rejuvenates aged brains by reducing BEC-mediated inflammation and VCAM1+ BEC-mediated reduction in NPC proliferation.