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Exercise induces BDNF, improves learning and reduces
β-amyloid
Carl W. CotmanInstitute for Brain Aging
University of California, Irvine
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Behavioral Interventions: The New Direction
Exercise
Mental Activity
Diet
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Outline
Part 1. Can exercise induce neurotrophic factors and improve learning?
Part 2. Can exercise reduce pathology in a AD transgenic mouse and improve learning?
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BDNF (Brain Derived Neurotrophic Factor) is a Synaptic Modulator:
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BDNF – Brain Derived Neurotrophic Factor
• Necessary for learning and long term synaptic change
• Stimulates synaptic growth and neurogenesis
• Protects neurons from injury How to get more?• Simple - exercise
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Is BDNF increased by exercise in the brain ?
• Where? And how fast and long lasting?
• How much exercise?
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Exercise increases BDNF mRNAHIPPOCAMPUS:
Rats: 1 week exercise (male sprague-dawley, 3 months)
Berchtold et al., 2002
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Time course of BDNF Protein Induction
0
255075
100125150
175200
225250
0
255075
100125150
175200
225250
2 0 4 7 14 28 72
DAILY EXERCISE
* *****
***
0 7 14 28
*
**
ALTERNATING DAYS
BD
NF
Pro
tein
(%
Sed
enta
ry)
Days Days
Berchtold, et al., submitted
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So..what is the functional significance?
• Learning?
• Stress Relief?
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Exercise Enhances Learning in the Morris Water Maze
0
20
40
60
80
100
120
Tim
e to
rea
ch p
latf
orm
(sec
)
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
Days of training
Sedentary
Exercising
* p < 0.05
**
**
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Blocking BDNF action (anti-TrkB) during the exercise period on memory retention using the probe trial on the Morris Water Maze task
(Vaynman, et al., 2004)
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Can exercise prevent the stress induced reduction in BDNF?
• Animals given 3 wks. of voluntary running• Subjected to acute immobilization stress• Circulating corticosterone and brain BDNF
measured
Hypothesis: Exercise will offset the effect of acute stress, possibly via a reduction in levels of circulating corticosterone.
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At 10 hours post-stress, BDNF is decreased in stressed animals, but remains elevated in animals that had prior exercise
0
20
40
60
80
100
120
140
160
180
200
Nor
mal
ised
leve
l of
BD
NF
pro
tein
(%
of
sede
ntar
y) ±
sta
ndar
d er
ror
at t
en h
ours
ControlSedentary
ControlExercising
StressedSedentary
StressedExercising
*
*
*
* Significantly different (p<0.05) from control sedentary
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Many plasticity genes are regulated by BDNF,e.g.,
• Synapsin: Regulates presynaptic vesicle availability Modulates neurotransmitter release into synapse
» Block TrkB in vivo suppresses exercise-induction of synapsin mRNA (Gomez-Pinilla, 2003)
• CREB: Transcription factor, drives downstream gene expression Important in LTP, learning and memory
» Block TrkB in vivo suppresses exercise-induction of CREB (Gomez-Pinilla, 2003)
• NR2b: subunit of glutamate receptor (NMDA)Overexpression enhances LTP and improves learning» Slice culture: BDNF increases NR2b protein
• NARP: Trafficking/insertion of glutamate receptors in PSD,critical to LTP and learning» Slice culture: BDNF increases NARP protein
• COX-2: traditionally known for immune functionRole in plasticity: localized to dendrites» Slice culture: BDNF increases COX-2 protein
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Practical Questions• How long lasting is the increase after
stopping exercise?• How frequent is necessary• Can the increase be recovered
rapidly if exercise is stopped for a peroid?
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Is there a molecular memory for exercise?
• Many of the gene changes including CREB are linked to learning and memory
• Is the experience of exercise encoded so to allow the brain to learn to respond?
Thus, if so exercise may prime the brain to respond to experiences, and induce a “state of readiness”.
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How Often to Exercise?: Is there a Molecular Memory Exercise
Paradigm:• 14 days of exercise:
- Daily (during 2 weeks)- Alternating (during 4 weeks)
• Wheels locked:- 1 week, 2 weeks
• Second short run period (2 days)
• Note: 2 days exercise alone is not sufficient to increase BDNF
0
25
50
75
100
125
150
175
200
1 wk delay2 wk delay
Daily Alternating DaysSED
*** *** *** ***
BD
NF
Pro
tein
(%
sed
enta
ry)
• Prior Exercise Primes subsequent BDNF Responsiveness
• Priming effect endures at least 2 weeks• Equivalent Secondary Responsiveness if prior
exercise is Daily Regime or Alternating Days of Exercise
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HIPPOCAMPUS Genomic regulation Structural change
- vascular - neuronal - neurogenesis
Increased neuronal health
EXERCISE
Peripheral Factors
Blood Brain Barrier
EstrogenIGF-1
Raphe (5-HT)Locus coeruleus (NE)
BDNF
Glucocorticoids
Medial Septum
other plasticity genes
↑↑
(ACh/GABA)
Cotman & Berchtold Cotman & Berchtold (2002)(2002)
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Estrogen-deprivation reduces baseline BDNF gene expression (Berchtold, etal., E.J.
of Neurosc., 2001)
IntactOVX-3OVX-7
100
125
150
DG hilus CA3 CA1
0
25
50
75
***
*
*T
**
T
BD
NF
mR
NA
exp
ress
ion
(% In
tact
)
* p<.05 * ** p<.001 T p=.09
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Exercise-induced BDNF increase is lost after 7 weeks of
estrogen deprivation
0
25
50
75
100
125
150
175INTACT OVX-3 wk OVX-7 wk
BD
NF
mR
NA
exp
ress
ion
(% s
eden
tary
Inta
ct)
***
***
SedentaryExercise
*** significantly different from sedentary p<.005
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Estrogen-replacement increases BDNF mRNA level
BD
NF
mR
NA
exp
ress
ion
(%
sed
enta
ry In
tact
)
200
0
25
50
75
100
125
150
175
225
DG hilus CA3 CA1
OVX-7
OVX-7/E
T
***
***
*** p<.005 T p=.08
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Exercise Further Increases BDNF, Specifically in the DG
DG hilus CA3 CA10
50
100
150
200
**T
SEDEX
BD
NF
mR
NA
exp
ress
ion
(%
sed
enta
ry In
tact
)
** p<.005 T p=.06
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Hormone replacement(17-beta Estradiol)
Restores Running Behavior
0
500
1000
1500
2000
2500
3000
3500
1 2 3 4 5
OVXOVX/EbetaINTACT
*
**
**
*T
Days
nigh
tly ru
nnin
g di
stan
ce
(met
ers)
* p<.05 OVX vs Intact ** p<.005 OVX vs Intact, 17-beta
T p =. 07 intact vs 17-beta
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ESTROGENPHYSICAL ACTIVITY
BDNF
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Is exercise effective in AD transgenic models ?
• Will voluntary running improve learning and memory?
• Stimulate neurogenesis?• Reduce β-amyloid in the brain?
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Animal model
• Widespread plaque deposition, including the hippocampus andcortex
Chishti et al., JBC 276: 21562-21570, 2001.
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Voluntary Exercise Paradigm (Adlard, etal., 2005)
• Utilized TgCRND8 mouse model
• Voluntary access to running wheels (animals run ~3 miles/day)
• Short-term running- start at 6 weeks of age- sacrifice four weeks later
• Long-term running- start at 6 weeks of age- sacrifice 5 months later
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Exercise improves the performance of TgCRND8 animals in the Morris water maze
0
5
10
15
20
25
30
35
40
45
50
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6Ave
rage
esc
ape
late
ncy
(sec
onds
) ± st
anda
rd
erro
r
SedentaryExercise
*
*
*
* p<0.02
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Long-term running reduces ß-amyloid load in TgCRND8 animals
(by immunohistochemistry)
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Long-term running reduces ß-amyloid load in TgCRND8 animals
(by ELISA)
0
20
40
60
80
100
120
140
Aß1-40 Aß1-42Form
ic-a
cid
extr
acta
ble
cort
ical
am
yloi
d (%
of s
eden
tary
)
SedentaryExercise
* *
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Long-term running enhances neurogenesis in TgCRND8 animals
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Mechanism: Long-term running had -
• no effect on steady-state levels of the amyloid precursor protein, APP
• no effect on secretase activity levels (α, β, γ)
Does short term running affect APP processing?
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Short-term running mediates APP processing
0
20
40
60
80
100
120
Aß1-40 Aß1-42
Perc
en
tag
e o
f se
den
tary
Sedentary
Exercise
0
20
40
60
80
100
120
alpha-CTF beta-CTF
Perc
en
tag
e o
f se
den
tary
Sedentary
Exercise
• no effect on total APP
• no effect on secretase activity (α, β, γ)
• no effect on neprilysin or IDE
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Summary
• BDNF increases with exercise in the hippocampus within a few days and lasts
• BDNF induction can be rapidly restored by a brief period of exercise even after exercise is stopped for weeks
• Exercise improves the rate of learning• Exercise reduces β-amyloid in the
hippocampus and cortex• Exercise alters APP processing
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Summary Part 2
• Exercise in a transgenic AD mouse improves learning
• Exercise reduces β-amyloid in the hippocampus and cortex
• Exercise alters APP processing
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Diet? What effect does an antioxidant
diet have on cognition?
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Can antioxidants and/or Exercise/Environmental Enrichment
Delay the Development of Age Dependent Cognitive Dysfunction and Neuropathology in Canines?
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Canine Antioxidant Diet
• Antioxidants• dl-alpha tocopherol acetate-
1050 ppm (20 mg/kg - 800 IU
• Stay-C (ascorbyl monophosphate)-100 ppm
• Spinach, carrot granules, tomato pomace, citrus pulp, grape pomace - 1% each in exchange for corn (Increased ORAC by 50%)
Mitochondrial cofactors• dl-Lipoic acid - 135 ppm (2.7
mg/kg)
• l-carnitine,Acetyl-car-300 ppm (6 mg/kg)
ROS
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Enrichment Protocol
• Play toys• kennelmate• 3x20 min walks• additional cognitive
experience
Controls
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6 months
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Oddity Discrimination Learning as a Function of Age
Task
Oddity -1 Oddity -2 Oddity -3 Oddity -4
Err
ors
to C
riter
ion
(Mea
n)
0
20
40
60
80
100
120
140
Young Dogs Old Dogs
Aged dogs make more mistakes as task complexity increases .
Learning Is Impaired in Old Canines
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E ffe c t o f d ie t o n o d d ity d is c r im in a tio n in a g e d b e a g le s
O d d ity ta s k0 1 2 3 4 5
Err
ors
to c
riter
ion
0
5 0
1 0 0
1 5 0
2 0 0 C o n tro l A n tio x id a n t
*
*
Diet fortified animals make few mistakes as task difficulty increases
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Is the intervention able to “reverse” age related
cognitive dysfunction?
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Spatial Memory and Treatment
P<.05
Year of Study
Year 1 Year 2 Year 3
Err
ros
to C
riter
ion
0
50
100
150
200
250
300
C/C C/E A/C A/E
P<.09
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What effect, if any, do the treatments have on brain
pathology?
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Effect of Antioxidant Diet on Total Amyloid Load (6E10)
By Brain Region
Brain Region
Prefrontal Entohrinal Parietal Occipital
Am
yloi
d Lo
ad (%
)
0
2
4
6
8Control Diet Antioxidant Diet
Entorhinal
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Conclusion
• A growing clinical literature suggests that exercise and diet can delay the onset of cognitive decline and AD
• Animal models show that exercise induces BDNF, a key plasticity and neuroprotecivefactor
• Animal models show that exercise and diet can reduce β-amyloid levels
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Summary Part 3
• A diet enriched in mitochondrial antioxidants improves learning in aged dogs
• Reduces β-amyloid accumulation• Diet plus environmental enrichment is
better than either alone
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Reduced reactive oxygen species (ROS) production by mitochondria in
treated aged dogs
Time5 min 10 min 15 min%
Incr
ease
in R
eact
ive
Oxy
gen
Spec
ies
Prod
uctio
n
0
200
400
600
800
1000
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1400 YoungOld ControlOld Antioxidant
ROS
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Long-term running enhances neurogenesis in TgCRND8 animals
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Is there a molecular memory for exercise?
• Exercise may prime the brain for learning and induces a state of readiness?
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exercise seems to prime the brain to respond to experiences, induce a “state of readiness”.
Is there a molecular memory for exercise?
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BDNF is a Synaptic Modulator
• Is BDNF induced by exercise and where in brain?
• How much exercise?
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Exercise increases BDNF mRNAHIPPOCAMPUS:
Rats: 1 week exercise (male sprague-dawley, 3 months)
Berchtold et al., 2002
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Exercise increases BDNF protein
Distance (meters/night)50004000300020001000
0
60
120
180
240
300
360
BD
NF
(pg/
ml)
R2 = 0.771
D.
EX SED0
100
200
300B
DN
F (p
g/m
l) *C.
Group
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Many plasticity genes are regulated by BDNF,e.g.,
• Synapsin: Regulates presynaptic vesicle availability Modulates neurotransmitter release into synapse
» Block TrkB in vivo suppresses exercise-induction of synapsin mRNA (Gomez-Pinilla, 2003)
• CREB: Transcription factor, drives downstream gene expression Important in LTP, learning and memory
» Block TrkB in vivo suppresses exercise-induction of CREB (Gomez-Pinilla, 2003)
• NR2b: subunit of glutamate receptor (NMDA)Overexpression enhances LTP and improves learning» Slice culture: BDNF increases NR2b protein
• NARP: Trafficking/insertion of glutamate receptors in PSD,critical to LTP and learning» Slice culture: BDNF increases NARP protein
• COX-2: traditionally known for immune functionRole in plasticity: localized to dendrites» Slice culture: BDNF increases COX-2 protein
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Exercise “restores” some of the age-related losses in synaptic
proteins
50
75
100
125
150
PSD-95 VESL/homer COX-2 Synapsin
% Y
oung
Sed
enta
ry
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CNS and Peripheral Factors Interact with Exercise to Regulate
BDNF
Exercise Hippocampus Downstream functional changesBDNF
Medial Septum(ACh/GABA)
Locus Coeruleus (NE)Raphe (5-HT)
Peripheral Factors
Blood-Brain Barrier
IGF-1EstrogenGlucocorticoids
Cotman and Berchtold (2002), TINS
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Practical Questions• How long lasting is the increase after
stopping exercise?• How frequent is necessary• Can the increase be recovered
rapidly if exercise is stopped for a peroid?
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BDNF Protein Stability After Exercise Ends
Berchtold, et al., submitted
0
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SED
BD
NF
prot
ein
(% se
dent
ary)
0 1 3 7 14
Days after end of exercise (4 weeks Daily Exercise)
*** ***
* *Paradigm:• 4 weeks daily voluntary
exercise• Day 0 - end of exercise
period,- wheels locked
• Sacrifice on days 0,1,3,7,14 after end of exercise
• Protein levels assessed
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Time course of BDNF Protein Induction
0
255075
100125150
175200
225250
0
255075
100125150
175200
225250
2 0 4 7 14 28 72
DAILY EXERCISE
* *****
***
0 7 14 28
*
**
ALTERNATING DAYS
BD
NF
Pro
tein
(%
Sed
enta
ry)
Days Days
Berchtold, et al., submitted
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Is there a molecular memory for exercise?
• Many of the gene changes including CREB are linked to learning and memory
• Is the experience of exercise encoded so to allow the brain to learn to respond?
Thus, if so exercise may prime the brain to respond to experiences, and induce a “state of readiness”.
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Once exercise stops is the induction stored in molecular memory?!
0
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1 wk delay2 wk delay
Daily Alternating DaysSED
*** *** *** ***
BD
NF
Pro
tein
(%
sed
enta
ry)
Paradigm:• 14 days of exercise:
- Daily (during 2 weeks)- Alternating (during 4 weeks)
• Wheels locked:- 1 week, 2 weeks
• Second short run period (2 days)
• Note: 2 days exercise alone is not sufficient to increase BDNF
• Prior Exercise Primes subsequent BDNF Responsiveness
• Priming effect endures at least 2 weeks• Equivalent Secondary Responsiveness if
prior exercise is Daily Regime or Alternating Days of Exercise
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So … What is the functional significance
of brain changes induced by exercise?
• Learning?• Stress relief?
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Exercise Enhances Learning in the Morris Water Maze
0
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Tim
e to
rea
ch p
latf
orm
(sec
)
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
Days of training
Sedentary
Exercising
* p < 0.05
**
**
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Is exercise an effective intervention in AD transgenic models ?
• Will voluntary running improve learning and memory?
• Reduce β-amyloid in the brain? • Stimulate neurogenesis?
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Voluntary Exercise Paradigm
• Utilized TgCRND8 mouse model
• Voluntary access to running wheels (animals run ~3 miles/day)
• Short-term running- start at 6 weeks of age- sacrifice four weeks later
• Long-term running- start at 6 weeks of age- sacrifice 5 months later
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Long-term running enhances the rate of learning in TgCRND8 animals
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Long-term running reduces ß-amyloid load in TgCRND8 animals
(by immunohistochemistry)
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Short-term running mediates APP processing
0
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Aß1-40 Aß1-42
Perc
en
tag
e o
f se
den
tary
Sedentary
Exercise
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alpha-CTF beta-CTF
Perc
en
tag
e o
f se
den
tary
Sedentary
Exercise
• no effect on total APP
• no effect on secretase activity (α, β, γ)
• no effect on neprilysin or IDE
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Why is learning and memory improved?
• Hypothesis – Neurogenesis?• Hypothesis – Aβ may impair CREB and
Elk transcriptional activity essential for learning and memory, e.g., induced by BDNF
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Long-term running enhances neurogenesis in TgCRND8 animals
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Recent clinical/ epidemiological findings
• Exercise and intellectual activities in mid life delay AD onset (Friedland, 2001)
• TV is associated with an increased risk of AD, 1.3X risk/hr of TV/day (Friedland, 2005)
• Exercise increases brain volume in select areas and larger brains are associated with those most fit (Kramer, 2004,2005)
• Women who get the most exercise show less cognitive decline (Yaffe, 2005;Grodstein, 2004)
• Those engaged in 4 or more physical activities have half the risk for AD, but mainly for ApoE4 carriers (Lyketsos, 2005)
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Exercise
Functional changes:Exercise
? -Increase BDNF -synaptic plasticity-Increased neuron number-Improve learning