A9 - Obesity-driven microglial activation and damage in the murine and human brain- functional role of cerebral lipid metabolism
Microglia, the brain’s immune competent phagocyte, crucially contributes to homeostasis, plasticity and learning by uptake of synaptic remnants and toxins such as iron and soluble beta-amyloid. As the microglial population is established during brain development and is only substituted by blood-borne monocytes upon massive damage, they exhibit signs of degeneration and eventually are lost in aged human brains.
The activation state of microglia is affected by obesity, western diet, and the microbiome which provides short-chain fatty acids required for microglial maturation. Further the peroxisomal brain metabolism of very long chain fatty acids (VLCFAs), polyunsaturated fatty acids (PUFAs), and cholesterol is influenced by nutrition factors. Thus, overeating could result in a microglial activation and agingcaused either by a toxic overload of accumulated bioactive metabolites such as proinflammatory prostaglandins or an increased damage of peroxisomes resulting in anaccumulation of VLCFAs and PUFAs. Given the crucial role of microglia inbrain function, this project aims i) the elucidation of microglial response to obesity in man and mice. Immunohistochemical, flow cytometric and ultrastructural studies will be used to detect immune activation and senescence in different brain areas.ii) the identification and quantification of functionally relevant fatty acid metabolites and sterols accumulating in the brain of mice on high-fat diet and human brains using a targeted metabolomics approach applyingliquid chromatography-tandem mass spectrometry. In addition, cerebral areas prone to microglial damage and loss shall be correlated with its respective metabolic profile.
The leading hypothesis of this project is that nutrition-induced cerebral accumulation of fatty acids, related bioactive lipids and their metabolites can promote microglial senescence and loss, e.g. by causing vascular stiffness and/or peroxysomal damage.
Figure 1. Iba-1 staining shows microglial morphology at different stages of Alzheimer’s disease [Braak&Braak I in (C) and Braak&Braak VI in (D)], in the non-demented old brain (B) and the young brain (A) in representative pictures taken from the hippocampal region. Normal microglia with thin and ramified branches can be seen in the young brain (A), whereas the older individual shows a loss of branches and ramification (B). In AD, microglial cells exhibit spheroid formation and a shortening of branches (C, D). From Tischer et al. (Glia 2016).
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