Institute of Anatomy

Obesity-driven microglial activation – functional role of cerebral sterol 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.

Prof. Dr. med. Ingo Bechmann
In cooperation with Prof. Dr Uta Ceglarek, Dr. Kerstin Immig, Dr. Judith Leyh und Dr. Julia Lier
Funded by SFB 1052

Publications

Phone: +49 341 - 97 22081
E-Mail: ingo.bechmann@medizin.uni-leipzig.de

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

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).

MICROGLIA

Ingo Bechmann in cooperation with Jens Eilers and Nicole Kaiser
Funded by DFG

Pruning, the elimination of excess synapses, is a phenomenon of central importance for a correct wiring of the central nervous system. Disturbance in this strictly regulated process could be the cause of human neurological and psychiatric diseases.

Recent studies give evidence that glia cells not only play a role at removing cell debris but also may play a more active role in pruning. Our group studies mouse lines with glia cell reporter constructs as well as mice with known pruning defect to point out the role of glia cells and related signaling-cascades.

Publications

1. Leyh J, Winter K, Reinicke M, Ceglarek U, Bechmann I, Landmann J. Long-term diet-induced obesity does not lead to learning and memory impairment in adult mice. PLoS One. 2021 Sep 29;16(9):e0257921.

2. Leyh J, Paeschke S, Mages B, Michalski D, Nowicki M, Bechmann I, Winter K. Classification of Microglial Morphological Phenotypes Using Machine Learning. Front Cell Neurosci. 2021 Jun 29;15:701673.

3. Kulow C, Reske A, Leimert M, Bechmann I, Winter K, Steinke H. Topography and evidence of a separate "fascia plate" for the femoral nerve inside the iliopsoas - A dorsal approach. J Anat. 2020 Dec 25.

4. Streit WJ, Khoshbouei H, Bechmann I. The Role of Microglia in Sporadic Alzheimer's Disease. J Alzheimers Dis. 2020 Dec 23.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.