# Vascular Mechanisms of Dementia: Cell-Type Specific Therapeutic and Imaging Strategies

> **NIH NIH RF1** · YALE UNIVERSITY · 2022 · $2,352,735

## Abstract

ABSTRACT:
Neuropathological studies in dementia frequently show mixed features including classical Alzheimer's hallmarks,
cerebral amyloid angiopathy (CAA), microhemorrhages, and microinfarcts, highlighting the complexity and
importance of vascular mechanisms in neurodegeneration. The precise mechanisms leading to CAA,
microvascular degeneration, and dysregulated cerebral blood flow (CBF) are poorly understood. The cellular
constituents of blood vessels include endothelial and mural cells (smooth muscle cells or pericytes), all of which
have critical roles in CBF regulation and blood-brain barrier maintenance. While these cells are prominently
affected in neurodegeneration, there are currently no specific therapeutic strategies for protecting them. A key
objective of this application is to develop innovative strategies to therapeutically target and image the various
vascular cellular components to improve our understanding of mechanisms leading to dementia. Specifically, we
aim to complete proof-of-concept studies with a focus on potential mechanisms of cytotoxicity mediated by iron
metabolism/reactive oxygen species (ROS) that may lead to microvascular degeneration. We aim to develop
and test compounds that can preferentially target brain pericytes, smooth muscle cells, and endothelial cells with
the goal of reducing intracellular free iron and ROS toxicity and ameliorating microvascular degeneration. These
cell-type specific compounds will also be tested to determine their potential to be used as probes for deep tissue
brain imaging in preclinical studies. To achieve this, we have assembled a multidisciplinary team at the interface
of neurovascular biology and chemistry and propose a comprehensive set of experiments that combine intravital
brain microscopy, chemical synthesis, single-cell transcriptomics, and animal models of CAA and microvascular
pathology. This project has the potential for identifying targets and strategies for ameliorating microvascular
degeneration that could significantly impact our mechanistic understanding and therapeutic approaches for
vascular dementia.

## Key facts

- **NIH application ID:** 10523230
- **Project number:** 1RF1NS128953-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Jaime Grutzendler
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,352,735
- **Award type:** 1
- **Project period:** 2022-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10523230

## Citation

> US National Institutes of Health, RePORTER application 10523230, Vascular Mechanisms of Dementia: Cell-Type Specific Therapeutic and Imaging Strategies (1RF1NS128953-01). Retrieved via AI Analytics 2026-06-24 from https://api.ai-analytics.org/grant/nih/10523230. Licensed CC0.

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