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

Presynaptic Neuron Postsynaptic Neuron Astrocyte Capillary Lactate 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

Brain

Brain

Brain

Brain

Lactate No Lactate Lactate No Lactate

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

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

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

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

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

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

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

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

Magnetic Resonance Spectroscopy

p<0.05

p<0.05 p<0.05

p<0.005

p<0.05

Relative TNFa Expression 1.2 p<0.05 1 0.8 Relative TNFa Expression (SEM) 0.6 0.4 0.2 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 36

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