Browsing by Author "Rawji, Khalil Sherali"

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    Altering the Lesion Microenvironment to Promote Remyelination in Aging Mice
    (2018-10-22) Rawji, Khalil Sherali; Yong, Voon Wee E.; Midha, Rajiv; Nguyen, Minh Dang
    Remyelination is diminished with aging, posing a significant challenge to therapy in white matter diseases. This decrease in remyelination is due to an impairment in oligodendrocyte progenitor cell maturation and is associated with a dysregulated innate immune response. Macrophages/microglia are components of this innate immunity and are essential to remyelination, as these cells release growth factors and clear inhibitory molecules such as myelin debris. Prior studies have shown that aging lesions have less recruitment of macrophages/microglia and less phagocytosis of myelin debris. It is unknown, however, if the dynamic properties of aging macrophages/microglia are altered within the lesion and whether other inhibitors of remyelination such as the chondroitin sulfate proteoglycans accumulate with aging. In this thesis, we sought to address these questions as well as describe two novel therapeutic strategies to rejuvenate remyelination in the aging central nervous system. We used the lysolecithin model of demyelination in young (2 – 3 months) and aging (9 – 12 months) mice and employed a novel ex vivo spectral multiphoton live imaging technique to examine the dynamic properties of macrophages/microglia. We found that aging macrophages/microglia have impaired process extension and are significantly less motile within the lesion microenvironment. Furthermore, we observed that lesions from aging mice display a significant accumulation of chondroitin sulfate proteoglycans and a decrease in the expression of several proteases. Finally, we have identified two different therapeutic strategies to enhance remyelination in the aging CNS. We have developed a novel inhibitor of chondroitin sulfate proteoglycans, peracetylated-4,4-difluoro-N-acetylglucosamine, and have found that the administration of this compound to aging mice enhances the recruitment of oligodendrocyte progenitor cells within the lesion. Second, we have discovered from a drug screen of 1040 compounds a clinically-approved medication, niacin, that significantly enhances macrophage/microglia cytokine secretion, phagocytosis, and chemotaxis in vitro. Treatment of aging mice with niacin significantly promotes macrophage/microglia phagocytosis of myelin debris and increased remyelination. The results within this thesis reveal a novel deficiency of macrophage/microglia dynamics within demyelinated lesions, describes a previously undescribed accumulation of inhibitory chondroitin sulfate proteoglycans, as well as identifies two innovative therapeutic strategies to rejuvenate remyelination in the aging CNS.