Inhibiting Ca2+ channels in Alzheimer's disease model mice relaxes pericytes, improves cerebral blood flow and reduces immune cell stalling and hypoxia

Nils Korte; Anna Barkaway; Jack Wells; Felipe Freitas; Huma Sethi; Stephen P Andrews; John Skidmore; Beth Stevens; David Attwell

doi:10.1038/s41593-024-01753-w

Inhibiting Ca²⁺ channels in Alzheimer's disease model mice relaxes pericytes, improves cerebral blood flow and reduces immune cell stalling and hypoxia

Nat Neurosci. 2024 Sep 18. doi: 10.1038/s41593-024-01753-w. Online ahead of print.

Authors

Nils Korte^{1

2}, Anna Barkaway³, Jack Wells⁴, Felipe Freitas³, Huma Sethi⁵, Stephen P Andrews⁶, John Skidmore⁶, Beth Stevens^{7

8}, David Attwell⁹

Affiliations

¹ Department of Neuroscience, Physiology & Pharmacology, University College London, London, UK. [email protected].
² Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
³ Department of Neuroscience, Physiology & Pharmacology, University College London, London, UK.
⁴ UCL Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London, UK.
⁵ Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, London, UK.
⁶ ALBORADA Drug Discovery Institute, University of Cambridge, Cambridge, UK.
⁷ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁸ Stanley Center, Broad Institute, Cambridge, MA, USA.
⁹ Department of Neuroscience, Physiology & Pharmacology, University College London, London, UK. [email protected].

PMID: 39294491
DOI: 10.1038/s41593-024-01753-w

Abstract

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⁺]_i early in AD may, thus, offer a therapeutic strategy to enhance brain energy supply and possibly cognitive function in AD.

Abstract

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