Myelination and Resilience Against Limbic Alpha-Synucleinopathy

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Abstract Lewy body disorders are hypothesized to involve the spread of a-synuclein aggregates through the central neuraxis, with cranial nerves I (primary olfactory nerve) and X (dorsal vagal nerve) as the most likely peripheral entry points. The olfactory and dorsal vagal nerves are unmyelinated, as are many of the neuronal groups most vulnerable to a-synucleinopathy (e.g., nigrostriatal efferents). Based on these observations, unmyelinated neurons were hypothesized to be selectively vulnerable to Lewy pathology, but this idea was largely overlooked for the last two decades. As a result, the relationship between the degree of myelination and resilience against a-synucleinopathy is still poorly understood. The process of myelination is known to lie under the control of microglial cells in neurodevelopment, but this link also remains open for exploration in Lewy body disorders. To fill these gaps, we will leverage our new sex-stratified, in vivo model of limbic a-synucleinopathy, in a series of studies appropriately scaled for the R15 mechanism and specifically designed for Ph.D., Pharm.D., and undergraduate students in the School of Pharmacy at Duquesne University. The following central hypothesis will be tested with a full-factorial experimental design: Myelination is linked to resilience against limbic α-synucleinopathy and is modified by microglia/macrophages. In Aim 1, our team will test the subhypothesis that markers of myelination in projection fibers of the olfactory bulb, such as the intrabulbar anterior commissure and lateral olfactory tracts, are inversely correlated with behavioral, histological, and biochemical disease-related outcomes in preformed fibril-infused mice. In Aim 2, we will test the subhypothesis that hypomyelination or demyelination amplifies limbic α-synucleinopathy at the histological and biochemical levels and worsens behavior deficits. In this Aim, mice heterozygous for myelin basic protein (MBP) will be infused with preformed fibrils in the olfactory bulb, as these mice display subtle hypomyelination-related deficits without shortened lifespans or severe behavior deficits. A separate cohort of fibril-infused mice will be fed the copper-chelator cuprizone in the diet, as this compound is known to demyelinate the anterior commissure and lateral olfactory tracts. In Aim 3, we will test the subhypothesis that microglia/macrophages improve myelination and temper limbic α-synucleinopathy in aging mice. The CSF1R antagonist PLX5622 will be fed to fibril-infused, aging mice to deplete brain cells of myeloid origin. This diet will be followed by PLX5622 withdrawal in one cohort to rejuvenate the aging microglial niche. We expect that microglial/macrophage depletion will worsen myelin condition and Lewy body disease-related outcomes, whereas microglial/macrophage repopulation will improve those measures. The proposed technical approaches can be completed by Ph.D., Pharm.D., and undergraduate students at Duquesne. Students in my lab have earned first-authorship on 19 papers, including 4 papers with undergraduate or Pharm.D. students as first authors. Regardless of the direction of the outcomes, the proposed work will shed light on the potential link between myelination and Lewy-related pathologies, while students will be trained in the conduct and dissemination of biomedical research on preclinical animal models of limbic Lewy body disease.