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).

Piotrowska A, Winter K, Carare RO, Bechmann I. Vital Functions Contribute to the Spread of Extracellular Fluids in the Brain: Comparison Between Life and Death. Front Aging Neurosci. 2020 Feb 11;12:15. 

Beuchel C, Becker S, Dittrich J, Kirsten H, Toenjes A, Stumvoll M, Loeffler M, Thiele H, Beutner F, Thiery J, Ceglarek U, Scholz M., Clinical and lifestyle related factors influencing whole blood metabolite levels - A comparative analysis of three large cohorts. Mol Metab. 2019 Nov;29:76-85.

Zelicha H, Kaplan A, Yaskolka Meir A, Tsaban G, Rinott E, Shelef I, Tirosh A, Brikner D, Pupkin E, Qi L, Thiery J, Stumvoll M, Kloting N, von Bergen M, Ceglarek U, Blüher M, Stampfer MJ, Shai I. The Effect of Wolffia globosa Mankai, a Green Aquatic Plant, on Postprandial Glycemic Response: A Randomized Crossover Controlled Trial. Diabetes Care. 2019 Jul;42(7):1162-1169

García-Cáceres C, Balland E, Prevot V, Luquet S, Woods SC, Koch M, Horvath TL, Yi CX, Chowen JA, Verkhratsky A, Araque A, Bechmann I, Tschöp MH. Role of astrocytes, microglia, and tanycytes in brain control of systemic metabolism. Nat Neurosci. 2019 Jan;22(1):7-14.

Joost E, Jordão MJC, Mages B, Prinz M, Bechmann I, Krueger M. Microglia contribute to the glia limitans around arteries, capillaries and veins under physiological conditions, in a model of neuroinflammation and in human brain tissue. Brain Struct Funct. 2019 Jan 31.

Wagner R, Dittrich J, Thiery J, Ceglarek U, Burkhardt R. Simultaneous LC-MS/MS quantification of eight apolipoproteins in normal and hypercholesterolemic mouse plasma. J Lipid Res. 2019 Feb 5. pii: jlr.D084301

Dittrich J, Beutner F, Teren A, Thiery J, Burkhardt R, Scholz M, Ceglarek U. Plasma levels of apolipoproteins C-III, A-IV, and E are independently associated with stable atherosclerotic cardiovascular disease. Atherosclerosis. 2018 Nov 9;281:17-24.

Reinicke M, Schröter J, lMüller-Klieser D,Helmschrodt C, Ceglarek U. Free oxysterols and bile acids including conjugates - Simultaneous quantification in human plasma and cerebrospinal fluid by liquid chromatography-tandem mass spectrometry. Analytica Chimica Acta, march 2018

Kälin S, Heppner FL, Bechmann I, Prinz M, Tschöp MH, Yi CX. Hypothalamic innate immune reaction in obesity. Nat Rev Endocrinol. 2015;11:339-51.

Koch M, Varela L, Kim JG, Kim JD, Hernandez-Nuno F, Simonds SE, Castorena CM, Vianna CR, Elmquist JK, Morozov YM, Rakic P, Bechmann I, Cowley MA, Szigeti-Buch K, Dietrich MO, Gao XB, Diano S, Horvath TL. Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature. 2015;519:45-50.

Yi CX, Gericke M, Krüger M, Alkemade A, Kabra DG, Hanske S, Filosa J, Pfluger P, Bingham N, Woods SC, Herman J, Kalsbeek A, Baumann M, Lang R, Stern JE, Bechmann I, Tschöp MH. High calorie diet triggers hypothalamic angiopathy. Mol Metab. 2012;1:95-100.

Burkhardt R, Kirsten H, Beutner F, Holdt M, Gross A, Teren A, Tönjes A, Becker S, Krohn K, Kovacs P, Stumvoll M, Teupser D, Thiery J, Ceglarek U, Scholz M. Integration of genome-wide SNP data and gene-expression profiles reveals six novel loci and regulatory mechanisms for amino acids and acylcarnitines in whole blood. PLoS Genet. 2015;11:e1005510.

Helmschrodt C, Becker S, Thiery J, Ceglarek U. Preanalytical standardization for reactive oxygen species derived oxysterol analysis in human plasma by liquid chromatography-tandem mass spectrometry. Biochem Biophys Res Commun. 2014;446:726-30.

Kortz L, Dorow J, Ceglarek U. Liquid chromatography-tandem mass spectrometry for the analysis of eicosanoids and related lipids in human biological matrices: a review. J Chromatogr B Analyt Technol Biomed Life Sci. 2014;964:1-11.

Ceglarek U, Dittrich J, Becker S, Baumann F, Kortz L, Thiery J. Quantification of seven apolipoproteins in human plasma by proteotypic peptides using fast LC-MS/MS. Proteomics Clin Appl. 2013;11-12:794-801.

Brauer R, Leichtle AB, Fiedler GM, Thiery J, Ceglarek U. Preanalytical standardization of amino acid and acylcarnitine metabolite profiling in human blood using tandem mass spectrometry. Metabolomics. 2011;7:344-52.

Prodinger C, Bunse J, Krüger M, Schiefenhövel F, Brandt C, Laman JD, Greter M, Immig K, Heppner F, Becher B, Bechmann I. CD11c-expressing cells reside in the juxtavascular parenchyma and extend processes into the glia limitans of the mouse nervous system. Acta Neuropathol. 2011;121:445-58.

Streit WJ, Braak H, Xue QS, Bechmann I. Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer's disease. Acta Neuropathol. 2009;118:475-85



Madlen Richter, PhD student

Judith Leyh, PhD student