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

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Presentation on theme: "Bioenergetic Manipulation for the Treatment of Neurodegenerative Diseases Russell Swerdlow, MD."— Presentation transcript:

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

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4 Glu Na+ K+ ATPADP Glucose Lactate ATP Gln ADP Lactate Capillary Presynaptic NeuronPostsynaptic Neuron Astrocyte Glucose

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6 Brain

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10 Lactate No Lactate Lactate No Lactate

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

12 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

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14 (A)(B) ** * (C)(D) * *

15 * * ** * (A) (B) (C)(D)(E) * * **

16 GlucosePyruvate Lactate ATP ADP Pyruvate Acetyl CoA NAD+NADH FAD FADH2 O2 H20 ADP ATP NAD+ NADH

17 (A)(B)(C) (D)(E)(F) * * * #

18 COO- O= C CH 2 COO- HO-C-H CH 2 COO- +NADH + H + +NAD + L-MalateOxaloacetate Malate Dehydrogenase

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

20 Control NAD+ / NADH (SEM) 2 mM OAA p<0.005 SY5Y Cell NAD+/NADH

21 Relative ATP (SEM) Control 2 mM OAA p<0.01

22 p<0.05 p< Control2 mM OAA SH-SY5Y Cells

23 p<0.05 P=0.09 Magnetic Resonance Spectroscopy

24 p<0.05

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26 p<0.005

27 p<0.05

28 Relative TNFa Expression (SEM) CONTROL MOUSE BRAINS OAA-TREATED MOUSE BRAINS p<0.05

29 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

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36 2.5 mM β-HB Control

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

38 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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