University of California, Los Angeles (UCLA)

Molecular Effects of Metabolic Syndrome on White Matter and Microvasculature

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Obesity is a rapidly growing public health problem that increases the risk of cerebrovascular disease. A major way that obesity damages the brain is by damaging small cerebral blood vessels and increasing the likelihood of a small vessel lacunar stroke. These small vessel lacunar strokes mostly occur in brain white matter. However, the specific molecular pathways provoked by obesity that accelerate cerebrovascular disease are unknown. With the support of the Larry L. Hillblom Foundation, the Hinman Laboratory employs cell-specific transcriptional profiling, obesity and stroke modeling, and cell fate mapping with a goal of meaningful translational neuroscience discovery. Using these approaches, we have identified that obesity blocks the differentiation of the major stem cell in brain white matter, the oligodendrocyte precursor cell (OPC). We have shown that this obesity-induced block of OPC differentiation results in dysfunctional myelin and axons that primes the brain white matter to respond aggressively to a white matter stroke lesion. In obesity, stroke-responsive OPCs are more numerous and are impeded from repairing the brain by remyelination after stroke. In addition, we have established that obesity results in increases in several specific molecular pathways in cerebral blood vessels. We are currently working to show that one of these obesity-induced vessel pathways acts within the vascular-OPC niche to block OPC differentiation. This work will lead to novel biomarkers and therapeutics for age-related white matter changes and cerebral small vessel disease.