The Mechanism of Gray Matter Atrophy in Experimental Autoimmune Encephalomyelitis

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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.