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Pathogenic soluble tau peptide disrupts endothelial calcium signaling and vasodilation in the brain microvasculature

The accumulation of the microtubule-associated tau protein in and around blood vessels contributes to brain microvascular dysfunction through mechanisms that are incompletely understood. Delivery of nutrients to active neurons in the brain relies on capillary calcium (Ca2+) signals to direct blood f...

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Published in:Journal of cerebral blood flow and metabolism 2024-05, Vol.44 (5), p.680-688
Main Authors: Mughal, Amreen, Sackheim, Adrian M, Koide, Masayo, Bonson, Grace, Ebner, Grace, Hennig, Grant, Lockette, Warren, Nelson, Mark T, Freeman, Kalev
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Language:English
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cited_by cdi_FETCH-LOGICAL-c340t-e592ea66b2b06e1b163d304aa514cdabf6a08ebceb4400af8d516be3e73a22ce3
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container_issue 5
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container_title Journal of cerebral blood flow and metabolism
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creator Mughal, Amreen
Sackheim, Adrian M
Koide, Masayo
Bonson, Grace
Ebner, Grace
Hennig, Grant
Lockette, Warren
Nelson, Mark T
Freeman, Kalev
description The accumulation of the microtubule-associated tau protein in and around blood vessels contributes to brain microvascular dysfunction through mechanisms that are incompletely understood. Delivery of nutrients to active neurons in the brain relies on capillary calcium (Ca2+) signals to direct blood flow. The initiation and amplification of endothelial cell Ca2+ signals require an intact microtubule cytoskeleton. Since tau accumulation in endothelial cells disrupts native microtubule stability, we reasoned that tau-induced microtubule destabilization would impair endothelial Ca2+ signaling. We tested the hypothesis that tau disrupts the regulation of local cerebral blood flow by reducing endothelial cell Ca2+ signals and endothelial-dependent vasodilation. We used a pathogenic soluble tau peptide (T-peptide) model of tau aggregation and mice with genetically encoded endothelial Ca2+ sensors to measure cerebrovascular endothelial responses to tau exposure. T-peptide significantly attenuated endothelial Ca2+ activity and cortical capillary blood flow in vivo. Further, T-peptide application constricted pressurized cerebral arteries and inhibited endothelium-dependent vasodilation. This study demonstrates that pathogenic tau alters cerebrovascular function through direct attenuation of endothelial Ca2+ signaling and endothelium-dependent vasodilation.
doi_str_mv 10.1177/0271678X241235790
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title Pathogenic soluble tau peptide disrupts endothelial calcium signaling and vasodilation in the brain microvasculature
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