# ApoE4 and mechanisms of diffuse white matter injury

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $694,617

## Abstract

Subcortical and periventricular white matter damage is a major cause of age-related cognitive
impairment, but the mechanisms remain elusive. Although the association with small vessel
disease leading to chronic ischemia is well recognized, the factors promoting white matter
damage are poorly understood. Located at the borderzone between separate arterial territories
and supplied by terminal arterioles, the deep white matter is highly vulnerable to hypoxia-
ischemia. ApoE is a lipid transport protein enriched in brain and present in three allelic variants
(2, 3, 4). Homozygosity for the 4 allele (4/4) is the main genetic risk factor for Alzheimer's
disease, but ApoE4 carriers also have increased risk for white matter lesions in the setting of
both vascular cognitive impairment and Alzheimer's disease. ApoE4 carriers have reduced
cerebral blood flow raising the possibility that cerebrovascular factors contribute their increased
propensity to white matter damage. However, it remains unclear whether ApoE4 disrupts vital
cerebrovascular mechanisms that assure adequate cerebral perfusion thereby promoting white
matter ischemic injury. Perivascular macrophages, bone marrow derived cells closely apposed
to the outer wall of cerebral arterioles, are enriched in ApoE receptors and are a powerful
source of reactive oxygen species and proinflammatory mediators. Therefore, we hypothesize
that ApoE4 promotes white matter damage by disrupting critical neurovascular mechanisms that
assure adequate cerebral perfusion, an effect mediated by perivascular macrophages through
oxidative stress and inflammation. Since TRPM2 channels are involved in macrophage
activation and neurovascular dysfunction, we will also examine their role. We will test the
following hypotheses: (a) ApoE4 disrupts vital homeostatic mechanisms regulating the cerebral
microcirculation; (b) perivascular macrophages contribute to the dysfunction through TRPM2
channels and ApoE receptors; (c) ApoE4 exacerbates hypoxic-ischemic white matter damage,
an effect mediated by perivascular macrophages. Studies are conducted in young and old mice
of both sexes with targeted replacement of mouse ApoE with human ApoE3 or 4. White matter
injury is produced in the corpus callosum by bilateral carotid artery stenosis. State-of-the-art
approaches are used to study neurovascular regulation, including a novel 3-photon imaging
method enabling us, for the first time, to simultaneously assess microvascular perfusion and
damage in the white matter of the corpus callosum in vivo. These studies will provide insight into
the mechanisms underlying the impact of ApoE4 on white matter damage, and may unveil new
therapeutic targets for a leading cause of cognitive dysfunction.

## Key facts

- **NIH application ID:** 9955372
- **Project number:** 5R01NS100447-05
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Costantino Iadecola
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $694,617
- **Award type:** 5
- **Project period:** 2016-09-30 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9955372

## Citation

> US National Institutes of Health, RePORTER application 9955372, ApoE4 and mechanisms of diffuse white matter injury (5R01NS100447-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9955372. Licensed CC0.

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