Pathogenic soluble tau peptide disrupts endothelial calcium signaling and vasodilation in the brain microvasculature
Year: 2024
Type: article
Abstract: 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 (Ca 2+ ) signals to direct blood flow. The initiation and amplification of endothelial cell Ca 2+ 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 Ca 2+ signaling. We tested the hypothesis that tau disrupts the regulation of local cerebral blood flow by reducing endothelial cell Ca 2+ signals and endothelial-dependent vasodilation. We used a pathogenic soluble tau peptide (T-peptide) model of tau aggregation and mice with genetically encoded endothelial Ca 2+ sensors to measure cerebrovascular endothelial responses to tau exposure. T-peptide significantly attenuated endothelial Ca 2+ 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 Ca 2+ signaling and endothelium-dependent vasodilation.
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: U.S. Department of Defense, American Heart Association, Henry M. Jackson Foundation, European Commission, Fondation Leducq, National Institutes of Health, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke
Awards: Functional deficits in neurovascular coupling in Alzheimer's disease, G1272653669, G1721003100, Diversity Supplement to 1RF1 NS128963, G178178799, Small vessel diseases in a mechanistic perspective: Targets for Intervention Affected pathways and mechanistic exploitation for prevention of stroke and dementia, G1898881650, G2184708656, Vermont Center for Cardiovascular and Brain Health, G421021930, G434337789, G4652114395, G4998324985, Functional deficits in neurovascular coupling in Alzheimer's disease, G5849909364, G6778132948, G6965823389, G7300092374, G757265334, Stroke-IMPaCT (Stroke – Immune Mediated Pathways and Cognitive Trajectories), G780303335, Ion Channel Dysfunction in Small Vessel Disease of the Brain, Capillaries as a Sensory Web that Controls Cerebral Blood Flow in Health and Disease, G8561324583, G991489597
OpenAlex ID: W4392293674