# Stalled capillary flow: a novel mechanism for hypoperfusion in Alzheimer disease

> **NIH NIH R01** · CORNELL UNIVERSITY · 2024 · $90,000

## Abstract

Summary
This grant focuses on understanding the causes and consequences of cerebral blood flow decreases in mouse
models of Alzheimer’s disease (AD). We recently showed there is increased incidence of the transient arrest of
circulating neutrophils in capillaries in the brain of AD mouse models. Because blood cells flow single file in
capillaries, this leads to stalled flow in the capillary segment. We serendipitously discovered that administration
of antibodies against the murine neutrophil surface protein, Ly6G, rapidly interferes with this neutrophil arrest,
decreasing the incidence of stalled capillaries by about two-thirds. We further found that this decrease in capillary
stalling was associated with a ~30% increase in cerebral blood flow, and was accompanied by a rapid
improvement (within hours) in performance on spatial and working memory tasks. In this grant, we are aiming
to:
 • Aim 1 – understand the cellular mechanisms contributing to neutrophil arrest in capillary segments, where
 we test three hypotheses: capillary constrictions caused by pericytes; binding to increased adhesion
 molecules on the endothelial surface; binding to exposed basement membrane and adhesion molecules
 in the widened gap between endothelial cells.
 • Aim 2 – evaluate the role of reactive oxygen species produced by NAPDH oxidase as an initiating factor
 in the arrest of neutrophils in capillaries.
 • Aim 3 – assess whether improving cerebral blood flow over time decrease amyloid-beta aggregation and
 neuropathology, taking advantage of knock-in mouse models of AD.
 • Aim 4 – use three photon excited fluorescence microscopy to assess capillary stalling and blood flow in
 the hippocampus
We have made major progress on Aims 1 and 2, with a recent publication and a second manuscript currently in
revision. We are conducting experiments for Aim 3 now, and we had our first hippocampal imaging working in
the last couple of months to start Aim 4. Unfortunately, we had a ~15 year old femtosecond laser system recently
fail. This laser is essential for the two-photon excited fluorescence microscopy that is the dominant experimental
approach we use in this work. We are requesting supplemental funding to help replace this laser.

## Key facts

- **NIH application ID:** 11063314
- **Project number:** 3R01AG049952-07S1
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Nozomi Nishimura
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $90,000
- **Award type:** 3
- **Project period:** 2015-05-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11063314

## Citation

> US National Institutes of Health, RePORTER application 11063314, Stalled capillary flow: a novel mechanism for hypoperfusion in Alzheimer disease (3R01AG049952-07S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11063314. Licensed CC0.

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