# Exploring the Role of Aging in Cerebral Ischemic Small Vessel Disease Using Notch3 Mutant Mice

> **NIH NIH UH3** · SCHEPENS EYE RESEARCH INSTITUTE · 2020 · $245,572

## Abstract

Cerebral small vessel disease (SVD) is one of the most prevalent neurological conditions of old age, and a
leading cause of stroke and cognitive impairment. In this application, we propose to investigate the role of
aging in the development of SVD in a mouse model of CADASIL (cerebral autosomal dominant arteriopathy
with subcortical infarcts and leukoencephalopathy), the most common genetic form of cerebral SVD. CADASIL
is caused by dominant mutations involving cysteine residues in the extracellular domain of the Notch 3
receptor, and is characterized by progressive degeneration smooth muscle cells (SMCs) in the small
penetrating arteries of the brain and accumulation of granular osmiophilic material (GOM) in vessel walls.
CADASIL patients start suffering recurrent ischemic strokes in their thirties or forties, and progressive cognitive
impairment and dementia starting in their fifties or sixties.
Based on the observations that: 1) patients with loss-of-function Notch 3 mutations do not have overt vascular
developmental abnormalities, and 2) heterozygous patients develop SVD much later in life than homozygous
patients, we hypothesize that the requirements for Notch 3 signaling are higher in old age than during
development or at younger ages. Therefore, it seems likely that aging will influence experimental outcomes
related to Notch 3 signaling manipulation, and that older mice will be better models to study the molecular and
cellular mechanisms linking Notch 3 signaling to SVD. In order to study this, we propose to test the hypothesis
that the impact of manipulating Notch 3 signaling on SVD-relevant phenotypes in mice will change with age.
In order to test our hypothesis, we will utilize mice that we generated and characterized in previous
publications (Arboleda-Velasquez et al., 2008; Arboleda-Velasquez et al., 2011), including a Notch 3 knockout
and two knockin models that allow inducible expression of either wild type human Notch 3 or human Notch 3
carrying the C455R CADASIL mutation, which lies in the Notch 3 ligand binding domain (LBD) (Arboleda-
Velasquez et al., 2002). Our analyses of these model mice show that the C455R mutation impairs signaling in
vitro and in vivo, leads to a robust SMC pathology, and (like other published CADASIL mutations located in the
LBD, C428S) displays dominant-negative properties.
In the UH2 phase of the project, we plan to: 1) breed mice carrying Notch 3 mutations and age them out to 24
months for use in the UH3 phase of the project and 2) determine feasibility by examining Notch 3 transgene
expression in vessels of aged mice. During the UH3 phase of the project, we propose the following
experimental goals: 1) to examine how age affects the impact of manipulating Notch 3 signaling on SVD by
monitoring the progression of SVD phenotypes and changes in SMC gene expression in aged and young
wildtype and Notch 3 mutant mice; and 2) to monitor the ability of an inducible wildtype human Notch 3
transgene to rescue SV...

## Key facts

- **NIH application ID:** 9990888
- **Project number:** 5UH3NS100121-05
- **Recipient organization:** SCHEPENS EYE RESEARCH INSTITUTE
- **Principal Investigator:** Joseph Arboleda-Velasquez
- **Activity code:** UH3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $245,572
- **Award type:** 5
- **Project period:** 2016-09-30 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990888

## Citation

> US National Institutes of Health, RePORTER application 9990888, Exploring the Role of Aging in Cerebral Ischemic Small Vessel Disease Using Notch3 Mutant Mice (5UH3NS100121-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9990888. Licensed CC0.

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