# The Mechanism of Gray Matter Atrophy in Experimental Autoimmune Encephalomyelitis

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $429,000

## Abstract

Project Summary/Abstract
 Multiple Sclerosis (MS) is a putative autoimmune disease of the central nervous system (CNS)
characterized by inflammation, demyelination, and gray matter (GM) atrophy. MS has long been regarded as a
disease of white matter (WM), nevertheless, GM involvement is an important component of the disease and
has a direct relationship to clinical disability. In fact, one of the most commonly occurring disabilities, cognitive
impairment, was better explained by atrophy than by T2 lesion volume and this appears to be true in both
relapsing remitting MS (RRMS) and benign MS, suggesting a silent progression of cognitive impairment
independent of MS clinical course. However, current immunomodulatory treatments have only had modest
success at reducing GM atrophy and disability accumulation in patients with MS. Thus, there is a critical barrier
to progress in developing neuroprotective treatments for MS – an understanding of the neuronal mechanisms
that lead to GM atrophy in order to successfully target neuroprotective therapeutics.
 It has been reported in the most commonly used mouse model of MS, experimental autoimmune
encephalomyelitis (EAE), that axonal damage in spinal cord lesions is caused at least in part by reactive
oxygen species (ROS) and reactive nitrogen species (RNS) produced by activated microglia and macrophages
at the site of lesions. Mitochondria are highly susceptible to oxidative injury, not only in the spinal cord, but also
in the cerebral cortex. We have observed activated microglia in the cerebral cortices of mice with EAE,
suggesting that oxidative stress may also be responsible for synaptic and neuronal loss in the cerebral cortex.
Thus, we hypothesize that oxidative stress causes mitochondrial dysfunction in the cerebral cortex and that
bioenergetic insufficiency due to mitochondrial dysfunction is in turn responsible for synaptic and neuronal loss
in the cerebral cortex. We will test this hypothesis by modulating the capacity of neurons to neutralize
superoxide, a major component of oxidative stress. We will also supplement neuronal bioenergetics during
disease to better understand the processes that underlie synaptic loss and GM atrophy.
 The proposed work will provide important new insights into the relationship between oxidative stress,
mitochondrial dysfunction and cortical GM atrophy that could someday be harnessed for therapeutic benefit.

## Key facts

- **NIH application ID:** 10196697
- **Project number:** 1R21NS121806-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Allan James MacKenzie-Graham
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $429,000
- **Award type:** 1
- **Project period:** 2021-04-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10196697

## Citation

> US National Institutes of Health, RePORTER application 10196697, The Mechanism of Gray Matter Atrophy in Experimental Autoimmune Encephalomyelitis (1R21NS121806-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10196697. Licensed CC0.

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