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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 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 Astrocyte Glucose Glucose Glucose Capillary
No Lactate Lactate Lactate No Lactate
ATP ADP Glucose Pyruvate Lactate Glycolysis Pyruvate Acetyl CoA O2 ADP NADH NAD+ H20 FAD FADH2 ATP
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
(A) (B) ** * ** (C) (D) * *
(A) (B) * ** * * (C) (D) (E) * * * *
ATP ADP Glucose Pyruvate Lactate NAD+ NADH Pyruvate Acetyl CoA O2 ADP NADH NAD+ H20 FAD FADH2 ATP
(A) (B) (C) # * (D) (E) (F) * *
COO- O= C CH2 COO- COO- HO-C-H CH2 COO- +NADH + H+ +NAD+ Malate Dehydrogenase Oxaloacetate L-Malate
ADP ATP Pyruvate Lactate Glucose NAD+ NADH Pyruvate Acetyl CoA O2 ADP NADH NAD+ H20 FAD FADH2 ATP
8 p<0.005 7 6 5 NAD+ / NADH (SEM) 4 3 2 1 0 Control 2 mM OAA SY5Y Cell NAD+/NADH
1.4 p<0.01 1.2 1 0.8 Relative ATP (SEM) 0.6 0.4 0.2 0 Control 2 mM OAA
SH-SY5Y Cells Control 2 mM OAA p<0.0005 p<0.05 p<0.0005 p<0.05
Magnetic Resonance Spectroscopy p<0.05 P=0.09
p<0.05 p<0.05
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
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
2.5 mM β-HB Control
BHB Acetyl CoA Fumarate BHB FADH2 FAD NAD+ Succinate Succinyl CoA NADH AcAc O2 ADP NADH NAD+ H20 FAD FADH2 ATP
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)