The pathological hallmarks of multiple sclerosis (MS) include lesions in the white and gray matter of the central
nervous system (CNS) comprised of areas of immune cell infiltration, reactive astrogliosis, axonal transection,
and demyelination. Proteins of the myelin sheath, such as myelin basic protein (MBP) and myelin
oligodendrocyte protein (MOG) have been extensively studied in MS pathogenesis; surprisingly, very little is
known about the changes to lipids components of the myelin sheath during the disease process, in
particular as it relates to changes in the composition of key myelin lipids during relapses, remission,
and progression of MS. Modifications in myelin lipids composition during disease relapses may critically
affect the progression of MS, for example by providing targets for lipid peroxidation. This may provide
druggable lipid-based targets, which have previously not been explored. There is an urgent unmet need in this
area.
Evidence in MS patients supports that increased lipid peroxidation occurs in the CNS. Moreover, it was shown
that combined treatment with glatiramer acetate (GA) and the potent antioxidant N-acetylcysteine (NAC)
decreased MS relapses as compared with GA treatment alone.
Studying myelin lipids in the CNS is technically challenging and therefore, we have developed a novel
approach using matrix-assisted laser-desorption/ionization time-of-flight (MALDI-TOF) mass
spectrometry imaging (MSI) for analysis of myelin lipids in situ. MALDI-TOF MSI is a label-free, two-
dimensional molecular imaging technique with < 20 µm spatial resolution capable of visualizing the molecular
spatial distribution, colocalization, and relative abundance of hundreds of targeted and untargeted analytes and
providing a molecular biological snapshot of the metabolic state of tissues. In support of the premise of this
proposal we have obtained exciting preliminary data revealing changes to myelin lipids in situ in the CNS
of mice with experimental autoimmune encephalomyelitis (EAE). Our results provide novel insights into
the CNS lipidome during neuroinflammation.
We will leverage our preliminary results and the unique combined expertise of our team in neuroinflammation
and MSI to test the hypothesis that the composition of myelin lipids does not return to baseline during
remission in relapsing-remitting EAE (RR-EAE) models of MS, and that the residual changes in lipid
composition play key roles in disease progression, for example via lipid peroxidation.
We will test our hypothesis by: (1) determining the effects of neuroinflammation on the composition and spatial
distribution of key CNS myelin lipids during relapses, remission, and progression of EAE; (2) determine the key
neuroinflammatory mechanisms driving changes in myelin lipid composition. Our proposal will fill a significant
gap in knowledge and address critical questions that will help develop better treatments for progressive MS.
