The brain is our most energy-hungry and metabolically active organ. It is responsible for our thoughts, ideas, movement and learning skills. Our brain is powered by 600 km of blood vessels that supply it with nutrients and remove waste products. However, the brain is also very fragile. Therefore, the blood vessels in the brain have evolved to form a narrow protective barrier, the blood-brain barrier (BEE), which restricts the movement of molecules in and out of the brain. It is essential that the brain can regulate its environment. On the one hand, pathogens or toxins are effectively prevented from entering the brain, but on the other hand, the necessary messengers or nutrients can pass through them unhindered. Given their close relationship, it is important that the brain and its vessels communicate widely. Recent have shown that blood vessels can detect the metabolic status of nearby neural cells. The researchers found that the MOF epigenetic regulator is needed to equip neurons with the right metabolic enzymes needed for fatty acid processing.
The brain usually used sugar for its basic metabolism, but fatty acids are also needed to build myelin and some components of cell membranes. Fatty acids are found in food and are used to generate energy and assemble complex lipids required in cell membranes. When MOF activity is defective, as occurs in neural development disorders, neurons cannot process fatty acids. This leads to their accumulation in the interstitial spaces between brain cells. In their studies, Asifa Akhtar’s team found that this imbalance in fatty acids is detected by neural blood vessels, stimulating them to mount a stress response by loosening the blood-brain barrier. If the metabolic imbalance remains, the leaking blood-brain barrier can induce disease. The researchers found that reducing three MOF members, Kansl2 or Kansl3 of the chromatin complex, unexpectedly leads to serious vascular defects and brain hemorrhages.
In their immediately preceding research, the scientists found that the loss of MOF lysine acetyltransferase or its associated members KANSL2 or KANSL3 leads to an accumulation of nuclear defects with genomic instability patterns including chromotripsis. This is a kind of digestion of the cell nucleus. This is because the nuclear histone H3 becomes hyper-methylated and this would stop the transcription of genes. In this new study, the researchers discovered another metabolic abnormality, the accumulation of long chain fatty acids (LCFA). Free LCFAs induce a cascade of inflammatory signaling in nearby vascular cells called pericytes, which make up the BEE. Pericytes show functional changes in response to LCFA-induced activation that cause vascular rupture. The damage is mediated by an immune-like receptor called the TLR4 receptor. Since TLR4 activates the nuclear factor NFκB to trigger the inflammatory response, the same damage is prevented by blocking TLR4.
The study lays the foundation for a better understanding of how neural cells and blood vessels talk to each other in the brain and illustrates how changes in the metabolic environment of a cell type in a complex organ can directly affect the functionality of surrounding cells and thus influence overall organ function. Bilal Sheikh, lead author of the study, Max Planck Institute of Immunobiology and Epigenetics, explained: “Something must tell the neural cells that there are nutrients around and they should activate the programs needed to process them. MOF goes to DNA and activates genetic programs that allow cells to process fatty acids in the brain. Our work shows that proper metabolism in the brain is fundamental for its health. A defective neural metabolic environment can induce vascular inflammation, dysfunction of the cells that form the blood-brain barrier and increased permeability. What can follow is the rupture of the neural blood vessels”.
This is particularly important, since rupture of the neural blood vessels is a feature of the onset of age-related diseases, such as Alzheimer’s disease and vascular dementia. Another condition with greater permeability of the brain membrane is migraine, a disease that affects millions of people around the world. There is no apparent association of migraine and blood vessel hemorrhage. However, a couple of analyzes reported that migraine could be significantly related to brain stroke risk. Higher protein lysine acetylation was also detected in tissues from aortic aneurysms, as reported in 2016 by a German research team. It is evident that this cell modification underlies the visible biological damage to the blood vessels. A better characterization of the molecular changes that induce vascular dysfunction will certainly help design better treatments for these debilitating diseases.
- By Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Sheikh BN et al., Akhtar A. Nat Cell Biol. 2020 Jun 15.
Karoutas A et al. Nat Cell Biol. 2019 Oct; 21(10):1248-1260.
Uemura MT et al. Front Aging Neurosci 2020 Apr 14; 12:80.
Sheikh BN, Akhtar A. Nat Rev Genet. 2019 Jan; 20(1):7-23.