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

J Cereb Blood Flow Metab. 2024 May;44(5):680-688. doi: 10.1177/0271678X241235790. Epub 2024 Feb 29.


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.

Keywords: Alzheimer’s disease; calcium; cerebral blood flow; dementia; endothelium.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / blood supply
  • Brain / metabolism
  • Calcium / metabolism
  • Calcium Signaling* / drug effects
  • Cerebrovascular Circulation* / drug effects
  • Cerebrovascular Circulation* / physiology
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Male
  • Mice
  • Microvessels* / drug effects
  • Microvessels* / metabolism
  • Vasodilation* / drug effects
  • tau Proteins* / metabolism


  • tau Proteins
  • Calcium