| Autor: |
Korte, Nils, Barkaway, Anna, Wells, Jack, Freitas, Felipe, Sethi, Huma, Andrews, Stephen P., Skidmore, John, Stevens, Beth, Attwell, David |
| Zdroj: |
Nature Neuroscience; November 2024, Vol. 27 Issue: 11 p2086-2100, 15p |
| Abstrakt: |
Early in Alzheimer’s disease (AD), pericytes constrict capillaries, increasing their hydraulic resistance and trapping of immune cells and, thus, decreasing cerebral blood flow (CBF). Therapeutic approaches to attenuate pericyte-mediated constriction in AD are lacking. Here, using in vivo two-photon imaging with laser Doppler and speckle flowmetry and magnetic resonance imaging, we show that Ca2+entry via L-type voltage-gated calcium channels (CaVs) controls the contractile tone of pericytes. In AD model mice, we identifed pericytes throughout the capillary bed as key drivers of an immune reactive oxygen species (ROS)-evoked and pericyte intracellular calcium concentration ([Ca2+]i)-mediated decrease in microvascular flow. Blocking CaVs with nimodipine early in disease progression improved CBF, reduced leukocyte stalling at pericyte somata and attenuated brain hypoxia. Amyloid β (Aβ)-evoked pericyte contraction in human cortical tissue was also greatly reduced by CaV block. Lowering pericyte [Ca2+]iearly in AD may, thus, offer a therapeutic strategy to enhance brain energy supply and possibly cognitive function in AD. |
| Databáze: |
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