Brain Metabolism and Neurodegeneration

Our research is focusing on energy substrate transport across the blood vessel wall and the contribution of organotypic endothelium for end-organ metabolism. In brain, we specifically hypothesize that cerebrovascular changes associated with an underlying metabolic dysfunction will act additively or synergistically to accelerate neuropathological development and cognitive decline.

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Previous work identified vascular endothelial growth factor-B (VEGF-B) as a central regulator of endothelial fatty acid (FA) uptake and transcytosis (Hagberg et al., 2010). Reducing VEGF-B signalling in models of obesity and diabetes prevents ectopic tissue lipid accumulation and improves insulin sensitivity, glucose homeostasis and ameliorates co-morbidities such as kidney nephropathy, fatty liver disease and stroke (Nilsson et al., unpublished) (Falkevall et al., 2017; Hagberg et al., 2012; Mehlem et al., 2016).

Increased endothelial FA uptake is paralleled by a concomitant decrease in endothelial glucose uptake capacity. Intriguingly, VEGF-B dependent impairment in glucose uptake is directly consequential to decreased low-density lipoprotein (LDL) uptake and membrane cholesterol loading (Moessinger, Nilsson et al., in revision). Together, these data depict VEGF-B as a potential regulator of brain glucose metabolism via its role in cholesterol transport and glucose partitioning.

Known environmental and genetic risk factors point to a metabolic aetiology underlying Alzheimer´s disease (AD). In fact, immense epidemiological, clinical and experimental studies have for a long time proposed a link between obesity and diabetes -e g dyslipidaemia, insulin resistance and glucose hypometabolism- and development and progression of AD (Merlo et al., 2010; Procaccini et al., 2016). We further speculate that brain glucose hypometabolism is connected to loss of blood-brain barrier (BBB) integrity and neuroinflammation; two coupled processes targetable with platelet-derived growth factor-C (PDGF-C) inhibition (Abrams et al., 2012; Adzemovic et al., 2013; Lewandowski et al., 2016; Su et al., 2008).

Team
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Ingrid Nilsson, PhD

Team Leader

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Benjamin Heller Sahlgren

PhD Student

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Mary Montenegro

Principle Technician