Upload
sakura
View
28
Download
1
Embed Size (px)
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 Presentation
Citation preview
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)