bioenergetic manipulation for the treatment of neurodegenerative diseases
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
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)