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Bioenergetic Manipulation for the Treatment of Neurodegenerative Diseases

Bioenergetic Manipulation for the Treatment of Neurodegenerative Diseases. Russell Swerdlow, MD. Presynaptic Neuron. Postsynaptic Neuron. Glu. Glu. Glu. Lactate. Glu. Lactate. Glu. Glu. Glu. Gln. Na+. Glu. Gln. Na+. Na+. K+. K+. Glu. ADP. ATP. Lactate. ATP. ADP. Glucose.

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Bioenergetic Manipulation for the Treatment of Neurodegenerative Diseases

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  1. Bioenergetic Manipulation for the Treatment of Neurodegenerative Diseases Russell Swerdlow, MD

  2. Presynaptic Neuron Postsynaptic Neuron Glu Glu Glu Lactate Glu Lactate Glu Glu Glu Gln Na+ Glu Gln Na+ Na+ K+ K+ Glu ADP ATP Lactate ATP ADP Glucose Astrocyte Glucose Glucose Glucose Capillary

  3. Brain

  4. Brain

  5. Brain

  6. Brain

  7. No Lactate Lactate Lactate No Lactate

  8. ATP ADP Glucose Pyruvate Lactate Glycolysis Pyruvate Acetyl CoA O2 ADP NADH NAD+ H20 FAD FADH2 ATP

  9. Inferences • Lactate mediates some “off target” exercise effects • Neurogenesis • Bioenergetic infrastructure changes • Some lactate effects mediated via mass action • Lactate may act as partial “exercise mimetic” • More intense exercise has bigger brain effect? • Relevance to exercise-in-AD trials • Different exercise regimens worth testing in AD • Lactate perhaps worth testing in AD

  10. (A) (B) ** * ** (C) (D) * *

  11. (A) (B) * ** * * (C) (D) (E) * * * *

  12. ATP ADP Glucose Pyruvate Lactate NAD+ NADH Pyruvate Acetyl CoA O2 ADP NADH NAD+ H20 FAD FADH2 ATP

  13. (A) (B) (C) # * (D) (E) (F) * *

  14. COO- O= C CH2 COO- COO- HO-C-H CH2 COO- +NADH + H+ +NAD+ Malate Dehydrogenase Oxaloacetate L-Malate

  15. ADP ATP Pyruvate Lactate Glucose NAD+ NADH Pyruvate Acetyl CoA O2 ADP NADH NAD+ H20 FAD FADH2 ATP

  16. 8 p<0.005 7 6 5 NAD+ / NADH (SEM) 4 3 2 1 0 Control 2 mM OAA SY5Y Cell NAD+/NADH

  17. 1.4 p<0.01 1.2 1 0.8 Relative ATP (SEM) 0.6 0.4 0.2 0 Control 2 mM OAA

  18. SH-SY5Y Cells Control 2 mM OAA p<0.0005 p<0.05 p<0.0005 p<0.05

  19. Magnetic Resonance Spectroscopy p<0.05 P=0.09

  20. p<0.05

  21. p<0.05 p<0.05

  22. p<0.005

  23. p<0.05

  24. p<0.05 1.2 1 0.8 Relative TNFa Expression (SEM) 0.6 0.4 0.2 0 CONTROL MOUSE BRAINS OAA-TREATED MOUSE BRAINS

  25. Inferences • OAA increases glucose utilization • Effects through mass action-based redox change • Spares respiration • Alters bioenergetic infrastructures • Warrants testing in neurodegenerative diseases • OAA PK study • OAA PD study

  26. 2.5 mM β-HB Control

  27. BHB Acetyl CoA Fumarate BHB FADH2 FAD NAD+ Succinate Succinyl CoA NADH AcAc O2 ADP NADH NAD+ H20 FAD FADH2 ATP

  28. Inferences • Betahydroxybutyrate can support respiration • Mass action-based increase in NADH • Mass action-based increase in FADH2 • May facilitate complex I or complex II fluxes • Compensate for a complex I defect? • Changes bioenergetic infrastructures • Clinical trials • MCT-based AD treatment currently marketed • Low carb diet suggested efficacy in MCI pilot trial • Ketogenic Diet Feasibility and Retention Trial (KDFART) • Diet-Induced Ketosis and Whey for AD (DIKWAD)

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