👤 Matti Marklund

Traumatic brain injury (TBI) often leads to impaired regulation of cerebral blood flow, which may be caused by pathological changes of the vascular smooth muscle cells (VSMCs) in the arterial wall. Moreover, these cerebrovascular changes may contribute to the development of various neurodegenerative disorders such as Alzheimer's-like pathologies that include amyloid beta aggregation. Despite its importance, the pathophysiological mechanisms responsible for VSMC dysfunction after TBI have rarely been evaluated. Here, we show that acute human TBI resulted in early pathological changes in leptomeningeal arteries, closely associated with a decrease in VSMC markers such as NOTCH3 and alpha smooth muscle actin (α-SMA).These changes coincided with increased aggregation of variable-length amyloid peptides including Aβ Show less

Fatty acid desaturases (FADS) catalyze the formation of unsaturated fatty acids and have been related to insulin sensitivity (IS). FADS activities differ between tissues and are influenced by genetic factors that may impact the link to IS. Genome-wide association studies of δ-5-desaturase (D5D), δ-6-desaturase (D6D) and stearoyl-CoA desaturase-1 (SCD) activities (estimated by product-to-precursor ratios of fatty acids analyzed by gas chromatography) in serum cholesterol esters ( Show less

When central nervous system axons are injured, regeneration is partly inhibited by myelin-associated inhibitors (MAIs). Following traumatic brain injury (TBI) in the rat, pharmacological neutralisation of the MAIs Nogo-A and myelin-associated glycoprotein (MAG) resulted in improved functional outcome. In contrast, genetic or pharmacological neutralization of the MAI receptors Nogo-66 receptor 1 (NgR1) or paired-immunoglobulin like receptor-B (PirB) showed an unaltered or impaired outcome following TBI in mice. The aim of the present study was thus to evaluate the MAI expression levels following TBI in mice. Quantitative reverse transcriptase PCR (qRT-PCR) was used to measure total RNA isolated from brains of young adult male C57BL/6 mice at one, three or seven days following controlled cortical impact TBI or sham injury. Hippocampal and neocortical tissue ipsi- and contralateral to the injury was analyzed for Nogo-A, oligodendrocyte-myelin glycoprotein (OMgp), MAG, and the MAI receptors PirB and NgR1, including its co-receptor Lingo1. Compared to sham-injured controls, PirB neocortical expression was significantly upregulated at one day and NgR1 expression downregulated at seven days post-TBI. In the hippocampus, transcriptional upregulation was observed in Nogo-A (one day post-injury), MAG and PirB at seven days post-injury. In contrast, the hippocampal transcripts of NgR1 and Lingo1 were decreased at seven days post-injury. The expression of OMgp was unaltered at all time points post-injury. These results suggest that early dynamic changes in MAI gene expression occur following TBI in the mouse, particularly in the hippocampus, which may play an inhibitory role for post-injury regeneration and plasticity. Show less

Identifying external factors that can be used to control neural stem cells division and their differentiation to neurons, astrocytes and oligodendrocytes is of high scientific and clinical interest. Here we show that the Nogo-66 receptor interacting protein LINGO-1 is a potent regulator of neural stem cell maturation to neurons. LINGO-1 is expressed by cortical neural stem cells from E14 mouse embryos and inhibition of LINGO-1 during the first days of neural stem cell differentiation results in decreased neuronal maturation. Compared to neurons in control cultures, which after 6 days of differentiation have long extending neurites, neurons in cultures treated with anti-LINGO-1 antibodies retain an immature, round phenotype with only very short processes. Furthermore, neutralization of LINGO-1 results in a threefold increase in βIII tubulin-positive cells compared to untreated control cultures. By using BrdU incorporation assays we show that the immature neurons in LINGO-1 neutralized cultures are dividing neuroblasts. In contrast to control cultures, in which no cells were double positive for βIII tubulin and BrdU, 36% of the neurons in cultures treated with anti-LINGO-1 antibodies were proliferating after three days of differentiation. TUNEL assays revealed that the amount of cells going through apoptosis during the early phase of differentiation was significantly decreased in cultures treated with anti-LINGO-1 antibodies compared to untreated control cultures. Taken together, our results demonstrate a novel role for LINGO-1 in neural stem cell differentiation to neurons and suggest a possibility to use LINGO-1 inhibitors to compensate for neuronal cell loss in the injured brain. Show less