Bioenergetic Manipulation for the Treatment of Neurodegenerative Diseases

Russell Swerdlow, MD

Glu

Glu

Glu

Glu

Glu

GluGlu

Glu

Glu

Na+

Na+ Na+K+K+

ATPADP

Glucose

Glucose

LactateATP

Gln

Gln

ADP

LactateLactate

Capillary

Presynaptic Neuron Postsynaptic Neuron

Astrocyte

GlucoseGlucose

0%

50%

100%

150%

200%

250%

0wk 1wk 2wk 3wk 4wk 5wk 6wk 7wk

Plasma lactate levels

*

* * *

20m/min22m/min

25m/min

Exhaustion

Rela

tive

leve

l

SED EX

A

B

0%

100%

200%

300%

400%

500%

600%* *

* *

Plasma lactate levels

Rela

tive

leve

l

00.20.40.60.8

11.21.41.6

mRN

Aex

pres

sion

SED EX VEH LAC

* *

PGC-1α PGC-1β PRC NRF-1 TFAM

Brai

n

00.20.40.60.8

11.21.41.6

MtD

NA/

nDN

A(1

8s rR

NA)

*

SED EX VEH LAC

*

16s rRNA ND2

Brai

n

00.20.40.60.8

11.21.4

mRN

Aex

pres

sion

*

SED EX VEH LAC

*

TNF-α/GAPDH VEGF-A/GAPDH

*

Brai

n

r = 0.665p < 0.001

Brain

Lactate

No Lactate

Lactate

No Lactate

Glucose Pyruvate Lactate

Glycolysis

ATPADP

PyruvateAcetyl CoA

NAD+ NADHFAD FADH2

O2

H20

ADP

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

Control MCI AD0

50

100

150

200

250

300

350

400

450

500G

luco

se-F

ree

Mito

chon

dria

l OC

R

(pm

ol O

2/m

in/m

g pr

otei

n +

SEM

)

Control AD+MCI0

50

100

150

200

250

300

350

400

450

500

Glu

cose

-Fre

e M

itoch

ondr

ial O

CR

(p

mol

O2/

min

/mg

prot

ein

+ SE

M)

(A) (B)

** * **

Control MCI AD0

10

20

30

40

50

60

Res

pira

tory

Lea

k R

ate

(% o

f bas

al O

2 co

nsum

ptio

n +

SEM

)

Control AD+MCI0

10

20

30

40

50

60

Res

pira

tory

Lea

k R

ate

(% o

f bas

al O

2 co

nsum

ptio

n +

SEM

)

(C) (D)

**

Control MCI AD0

0.2

0.4

0.6

0.8

1

1.2

Bas

al G

lyco

lysi

s R

ates

(+ S

EM)

Control MCI AD0

0.2

0.4

0.6

0.8

1

1.2

Gly

coly

sis

Cap

acity

Rat

es (+

SEM

)

* * ** *

(A) (B)

Control MCI AD0

0.2

0.4

0.6

0.8

1

1.2

Rel

ativ

e N

AD

+ (+

SEM

)

Control MCI AD0

0.2

0.4

0.6

0.8

1

1.2

1.4R

elat

ive

NA

DH

(+SE

M)

Control MCI AD0

0.2

0.4

0.6

0.8

1

1.2

NA

D+/

NA

DH

(+SE

M)

(C) (D) (E)

* ** *

Glucose Pyruvate LactateATPADP

PyruvateAcetyl CoA

NAD+ NADHFAD FADH2

O2

H20

ADP

ATP

NAD+ NADH

Control MCI AD0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6R

elat

ive

AD

P Fl

uore

scen

ce (+

SEM

)

Control MCI AD0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

AD

P/A

TP F

luor

esce

nce

(+SE

M)

Control MCI AD0.84

0.86

0.88

0.9

0.92

0.94

0.96

0.98

1

1.02

Rel

ativ

e A

TP F

luor

esce

nce

(+SE

M)

Control AD+MCI0

0.2

0.4

0.6

0.8

1

1.2

1.4

Rel

ativ

e A

DP

Fluo

resc

ence

(+SE

M)

Control AD+MCI0

0.2

0.4

0.6

0.8

1

1.2R

elat

ive

ATP

Flu

ores

cenc

e (+

SEM

)

Control AD+MCI0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

AD

P/A

TP F

luor

esce

nce

(+SE

M)

(A) (B) (C)

(D) (E) (F)

*

* *

#

COO-

O= C

CH2

COO-

COO-

HO-C-H

CH2

COO-

+NADH + H+ +NAD+

L-MalateOxaloacetate

MalateDehydrogenase

Glucose Pyruvate Lactate

ATPADP

PyruvateAcetyl CoA

NAD+ NADHFAD FADH2

O2

H20

ADP

ATP

NAD+ NADH

0

1

2

3

4

5

6

7

8

Control

NAD

+ /

NAD

H (S

EM)

2 mM OAA

p<0.005

SY5Y Cell NAD+/NADH

0

0.2

0.4

0.6

0.8

1

1.2

1.4Re

lativ

e AT

P (S

EM)

Control 2 mM OAA

p<0.01

Non-Glyc

olysis

ECAR

Glycolys

is ECAR (C

orrecte

d)

Glycolys

is Flux C

apac

ity (C

orrecte

d)

Glycolys

is Flux S

pare Cap

acity

0200400600800

100012001400 Control 2 mM OAA

ECA

R (m

pH/m

in +

SEM

)

p<0.05

p<0.05

p<0.0005

p<0.0005

Control 2 mM OAASH-SY5Y Cells

Pre OAA Treatment Post OAA Treatment2

2.1

2.2

2.3

2.4

2.5

2.6

2.7

2.8

Bra

in L

acta

te (u

mol

/gra

m w

et ti

ssue

+ S

EM)

p<0.05

Pre OAA Treatment Post OAA Treatment0

0.5

1

1.5

2

2.5

3

3.5

Bra

in G

luco

se (u

mol

/gra

m w

et ti

ssue

+ S

EM)

P=0.09

Magnetic Resonance Spectroscopy

Control OAA0

0.2

0.4

0.6

0.8

1

1.2

1.4

Brai

n SI

RT1

Expr

essio

n (S

EM)

p<0.05

Control OAA0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

Brai

n CR

EB E

xpre

ssio

n (S

EM)

Control OAA0

0.5

1

1.5

2

2.5

Brai

n BD

NF

Expr

essio

n (S

EM)

p<0.05

p<0.05

p<0.005

Control OAA0

0.2

0.4

0.6

0.8

1

1.2

1.4

Brai

n PG

C1a

Expr

essio

n (S

EM)

Control OAA0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

Brai

n CO

X4A1

Exp

ress

ion

(SEM

) p<0.05

0

0.2

0.4

0.6

0.8

1

1.2

Rela

tive

TNFa

Exp

ress

ion

(SEM

)

CONTROLMOUSE BRAINS

OAA-TREATEDMOUSE BRAINS

p<0.05

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

NAD+ NADHFAD FADH2

O2

H20

ADP

ATP

BHB

AcAc

SuccinylCoA

Succinate

Fumarate

FADFADH2

NAD+

NADH

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)