# Pathogenic soluble aggregated tau as a driver of brain vascular dysfunction in Alzheimer's disease

> **NIH VA I01** · OKLAHOMA CITY VA MEDICAL CENTER · 2024 · —

## Abstract

Energy substrates must be delivered to the brain continuously through its blood supply. Failure of this process
has devastating consequences because brain function depends on the timely delivery of energy substrates to
neurons through blood flow. Accumulating evidence suggests that Alzheimer’s disease (AD) is a multifactorial
heterogeneous disease driven by multiple pathophysiological contributors, including brain vascular dysfunction.
Consistent with this, decreased cerebral blood flow is an early biomarker of AD. There is an urgent need to
understand brain vascular mechanisms of AD since they may constitute the most therapeutically addressable
biological pathway underlying dementia. Tau protein, causally implicated in AD, stabilizes microtubules. In AD,
tau misfolds, destabilizing the microtubule cytoskeleton, and is then transferred trans-neuronally, promoting tau
aggregation and microtubule destabilization in target cells. We found, for the first time, that pathogenic tau is also
transmitted to brain microvascular endothelial cells, where it destabilizes microtubules, diminishes activity of the
endothelial form of nitric oxide synthase, induces endothelial cell senescence, and causes profound brain
vascular dysfunction in models of tauopathy. The mechanisms by which pathogenic tau induces brain
microvascular endothelial cell (BMEC) dysfunction and senescence, and the role of tau-induced BMEC
dysfunction and senescence in the etiology of AD have not been explored before. Our goal is to define the
mechanisms of pathogenic tau-induced brain vascular dysfunction and their involvement in AD, and determine
whether (a) removal of pathogenic tau or (b) removal of senescent brain microvascular endothelial cells could
be used to delay (or potentially treat) AD. Our hypothesis is that pathogenic tau transmission to BMEC drives
brain vascular dysfunction in AD by impairing BMEC function and by promoting BMEC senescence. We will
test our hypothesis with studies that will (Aim 1) identify tau-induced molecular alterations that result in brain
endothelial cell dysfunction and senescence; and (Aim 2) establish the therapeutic potential of (a) pathogenic tau
or (b) senescent brain microvascular endothelial cell removal in AD, and determine, in human brain, how
microvascular tau and molecular alterations identified in Aim 1 are linked to AD progression. Our work will
address an entirely new aspect of AD pathophysiology, the accumulation of tau in brain microvasculature and its
transmission to brain endothelial cells, that induces endothelial cell dysfunction and senescence, and will define
whether pathogenic tau and the cellular events it triggers can be targeted therapeutically. These studies are
significant, because once we know how pathogenic tau impairs brain vascular function we will be able to
manipulate those mechanisms in AD and other tauopathies. Our studies will pioneer research on a new cellular
target of tau toxicity -brain vascular endothelial cel...

## Key facts

- **NIH application ID:** 10807189
- **Project number:** 2I01BX002211-10A1
- **Recipient organization:** OKLAHOMA CITY VA MEDICAL CENTER
- **Principal Investigator:** Veronica Galvan
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2015-01-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10807189

## Citation

> US National Institutes of Health, RePORTER application 10807189, Pathogenic soluble aggregated tau as a driver of brain vascular dysfunction in Alzheimer's disease (2I01BX002211-10A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10807189. Licensed CC0.

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