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

4. 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

6. Brain

7. Brain

8. Brain

9. Brain

10. Lactate
No Lactate
Lactate
No Lactate

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

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

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

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

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

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

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

20. p<0.005 NAD+ / NADH (SEM) Control 2 mM OAA SY5Y Cell NAD+/NADH 8 76 5
NAD+ / NADH (SEM) 4 3 2 1
Control
2 mM OAA
SY5Y Cell NAD+/NADH

21. 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

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

23. Magnetic Resonance Spectroscopy

24. p<0.05

25. p<0.05
p<0.05

26. p<0.005

27. p<0.05

28. 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

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

36. 2.5 mM β-HB
Control 36

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

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)