# Exploring the origins of myelin abnormalities in normal ageing and in vascular dementia

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $724,723

## Abstract

According to the World Health Organization approximately 50 million people worldwide suffer from cognitive
disorders. The incidence of dementia increases with age, especially for those over 65. CNS white matter lesions
are also known to increase with age and to increase the risk of developing dementia. Vascular dementia (VD) is
the second most common cause of cognitive abnormalities in the elderly behind Alzheimer’s disease (AD). VD
has been associated with various cardiovascular maladies, which are thought to contribute to diffuse white matter
disease leading to dementia. The underlying hypothesis of this proposal is that the impact of the cytotoxic
environment created by disruptions to the CNS vasculature associated with aging and diverse cardiovascular
disorders are particularly detrimental to oligodendrocyte viability and function. We posit that the heightened
sensitivity to cellular stress that oligodendrocytes display due to their unique metabolic demands makes them
particularly vulnerable to the changing extracellular environment that develops with advancing age and in
response an altered cerebral circulation. The white matter abnormalities that occur as a consequence of
oligodendrocyte perturbation are likely critical to the development of neurodegenerative, cognitive and behavioral
changes. The goal of the current proposal is to a gain a mechanistic understanding of the impact of ageing and
cerebrovascular abnormalities on oligodendrocytes, both in humans and in mouse models. Our focus will be on
examining the role that intrinsic cytoprotective pathways play in the response of oligodendrocytes to the adverse
cytotoxic environment created by these conditions. We will focus on three cytoprotective pathways: the
integrated stress response (ISR) pathway is initiated by a variety of stresses including oxidative stress, hypoxia
and inflammation; the nuclear factor erythroid 2-related factor 2 (NRF2) pathway is activated in response to
oxidative stress; and the hypoxia-inducible factor 1 (HIF-1) pathway is the master transcriptional regulator of the
cellular response to hypoxia. We will examine human postmortem samples from individuals with vascular
dementia for activation of these pathways in oligodendrocyte lineage cells, and we will similarly assess their
activation in ageing mice, which are known to display oligodendrocyte and myelin deficiencies. We will also
examine a mouse model of heart failure with preserved ejection fraction (HFpEF) for oligodendrocyte and myelin
abnormalities linked to ISR, NRF2 and HIF activation. HFpEF is a common cardiovascular abnormality
associated with dementia. We will also use a genetic approach to further examine the response of these
cytoprotective pathways to the adverse CNS environment created by ageing and cerebrovascular abnormalities.
Together, these efforts will substantially increase our understanding of the response of oligodendrocytes to the
cytotoxic CNS environment created by ageing and cerebrova...

## Key facts

- **NIH application ID:** 10890253
- **Project number:** 4R01AG072080-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Margaret E Flanagan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $724,723
- **Award type:** 4N
- **Project period:** 2021-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10890253

## Citation

> US National Institutes of Health, RePORTER application 10890253, Exploring the origins of myelin abnormalities in normal ageing and in vascular dementia (4R01AG072080-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10890253. Licensed CC0.

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