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Male Wistar Rats (n=55) Age at recruitment; 8 weeks 18 received a control diet 19 received a Hcy enriched diet (1.7% homocystine) 18 received a methionine.

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Presentation on theme: "Male Wistar Rats (n=55) Age at recruitment; 8 weeks 18 received a control diet 19 received a Hcy enriched diet (1.7% homocystine) 18 received a methionine."— Presentation transcript:

1 Male Wistar Rats (n=55) Age at recruitment; 8 weeks 18 received a control diet 19 received a Hcy enriched diet (1.7% homocystine) 18 received a methionine rich diet (2.4% methionine) Duration of the study; 5 months Blood samples were collected Brain was isolated and one part (about 50 mg from the frontal area and the brain stem) was homogenized in acetic acid for SAM and SAH assay Phosphorylated Tau protein was tested in brain tissues, by using immunoflourescence microscope Effect of Dietary HHCY on Brain Metabolites; in-vivo Experiments Brain stem Frontal cortex

2 Plasma tHcy, mol/L 225 200 175 150 125 100 75 50 25 0 Met n=18 Hcy n=18 Control n=19 7.0 = median 74.4 112.9 * * Diet * p<0.001 compared to the control diet; compared to the Hcy group Effect of Dietary HHCY on Brain Metabolites; in-vivo Experiments 1.7% homocystine 2.4% methionine Male Wistar Rats (n=55) Age at recruitment; 8 wk duration 5 months Obeid et al., submitted

3 The diets caused disturbances in methylation markers in the brain (frontal cortex) Obeid et al., submitted 20 16 12 8 4 0 SAM/SAH ratio/g tissue 10.2 7.7 4.0 HCY N=18 Meth N=18 Control N=19 * * 1.7% homocystine 2.4% methionine Male Wistar Rats (n=55) Age at recruitment; 8 wk duration 5 months * P<0.01

4 Plasma folate, nmol/L SAM/SAH ratio in brain tissues 300280260240220200180160140 25 20 15 10 5 0 Frontal cortex R=0.36, p=0.007 Methylation Potential in Rat Brain correlates with plasma vitamins 900800700600500400300 25 20 15 10 5 0 Plasma vitamin B12, pmol/L Frontal cortex R=0.37, p=0.006

5 Experimental HHCY caused P-tau accumulation in rats brain 16B Control diet 1B Methionine rich diet (2.4%) 26B HCY rich diet (1.7%) Fontal Cortex, left hemisphere, fluorescence detection using PHF-Tau phosphorylated at serine 396 + Alexa flour 488 Axio Vision REL 4.4 Carl Zeiss® Homocystine diet N = 6 Methionine diet N = 6 Control diet N = 9 Optical density of P-tau protein, pixel 1250 1000 750 500 250 0 312 912 891 * * Experimental hyperhomocysteinemia decreases the methylation potential and increases P-tau accumulation in rat brain The methylation potential in rat brain correlates directly with serum folate and B12 but inversely with Hcy

6 A reduced methylation potential correlates with higher concentrations of markers of neurodegeneration, P-tau, APP, -amyloid and α-synuclein α-synuclein a new marker of neuronal degeneration in PD correlated inversely with SAM but positively with amyloid-β The cognitive performance in PD correlated directly with the methylation potential but inversely with amyloid-β HHCY in rats causes significant P-tau accumulation in brain The brain methylation potential correlates with serum folate and B12 P-tau accumulation in rats brain correlates with HCY + inversely with folate PP2A activity in rats brain correlates with folate + inversely with P-tau In conclusion, B-vitamin deficiency has via hypomethylation a significant impact on the process of neurodegeneration Summary / Final Comments

7 Methylation Protein P P P P Phosphorylation PP2A- activity Fats, oil sweets Folate B12, B6, Choline Tangling disease Functional proteins Tau P-tau APP pAPP NF-H pNF-H Impaired repair/control mechanisms DNA methylation β -Amyloid α-Synuclein PC;SP/PE Ubiquitin proteasome system PIMT; Pin-1 CH 3 C G X

8 Acknowledgements PD Dr. Markus Herrmann Dipl. Chem. J.P. Knapp Dr. Natascha Umanskaja Department of Clinical Chemistry M. Kasoha J. Schlundt Department of Neurology Financial Support HOMFOR PhD students Prof. K. Fassbender PD Dr. U. Dillmann P. Kostopoulus Jun.-Prof. Dr. Rima Obeid A Schadt

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