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.
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homeostasis and ameliorates co-morbidities such as kidney nephropathy, fatty liver disease and stroke (Nilsson et al., unpublished) (Falkevall et al., 2017; Hagberg et al., 2012; Mehlem et al., 2016).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).
Ingrid Nilsson, PhD
Benjamin Heller Sahlgren