animal models of neuroplasticity: or is it cognitive reserve? · age effects on mitochondrial...
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Animal Models of Neuroplasticity: or is it Cognitive
Reserve?
Carl W. Cotman Depts of Neurology and
Neurobiology and Behavior, University of California Irvine
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Student Definitions
• “Cognitive reserve is the concept used to describe patients who exhibit AD pathology without the associated cognitive defects.”
• “I will define brain cognitive reserve as functional compensation for AD pathology induced by enhancement of mental and physical activity.”
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Overview:
• Impact of an enriched environment on building reserve in a higher animal model
• Role of BDNF in reserve – enables learning and recall
• Molecular reserve in MCI – reserve in action?
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The aged canine as a model of human brain aging
• Canines develop learning and memory deficits beginning in middle age.
• Like humans, with age, canines: – show increased individual variability in cognition. – naturally accumulate beta-amyloid. – Accumulate oxidative damage (proteins, lipids)
and mitochondrial dysfunction • Represents an animal model of MCI
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Can Behavioral Enrichment/Exercise, and/or Diet, reduce the Development of Age-Dependent Cognitive Dysfunction in
Canines?
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Longitudinal Study
Aox Diet (-) Aox Diet (+)
Behavioral Enrichment (-)
N=12 Old N=12 Old
Behavioral Enrichment (+)
N=12 Old N=8 Young
N=12 Old N=9 Young
Old beagles – 8 to 12 years at start Young beagles – 2 to 5 years at start Treatment duration – 2.8 years
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Canine Antioxidant Diet Antioxidants
• dl-alpha tocopherol acetate-1050 ppm (20 mg/kg - 800 IU/day)
• Stay-C (ascorbyl monophosphate)-100 ppm or ~100 mg/day
• Spinach, carrot granules, tomato pomace, citrus pulp, grape pomace: 1% each in exchange for corn (Increased ORAC by 50%, equivalent to 4-5 servings of fruits and vegetables/day)
Mitochondrial cofactors • dl-Lipoic acid: 135 ppm (2.7 mg/kg)
• l-carnitine: 300 ppm (6 mg/kg)
ROS
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Enrichment Protocol
• Play toys • Kennelmate • 3-4 weekly walks • Additional cognitive
experience/education
Controls
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Discrimination learning: shape, color, size
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Discrimination Learning is impaired with age
• 10 trials/day • 40 training sessions • Criteria: 70% of trials
correct, 3 successive test sessions
Black/White discrimination
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Combined intervention (EE+AOX) prevents cognitive decline with age
Object Task: Size B/W discrim
EE = behavioral enrichment AOX = antioxidant diet
Reversal performance:
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Can the interventions “reverse”
age-related cognitive dysfunction?
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Spatial Memory improved by EE+AOX
Year of Study
Year 1 Year 2 Year 3
Errr
os to
Crit
erio
n
0
50
100
150
200
250
300
C/C C/E A/C A/E
P<.05
Control EE AOX EE+AOX
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Synapse Markers are increased in the combined treatment group (SNAP25)
Con AOX EE EE+AOX
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Age Effects on Mitochondrial Generation of ROS
Time (minutes)4 6 8 10 12 14 16
RO
S G
en
era
tion
0
200
400
600
800
1000
1200Young AnimalsAged Animals
p<.002
p<.002
p<.004
Head, Cotman, Sullivan, 2009
Mitochondrial Generation of ROS As a Function of Diet in Aged Dogs
Time (minutes)4 6 8 10 12 14 16
Ge
ne
ratio
n o
f R
OS
0
200
400
600
800
1000
1200
1400Control DietAntioxidant Diet
p<.064
p<.045
p<.035
Mitochondrial ROS production as a function of age and EE+AOX treatment
EE+ AOX
Untreated control
Aged
Young
AGE EE + AOX
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Enrichment+AOX reduces age-related oxidative damage:
SOD, superoxide to water; GST, detoxifies HNE
*
(Oppi, Cotman, et al., 2008)
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The Interventions reduce age-related Caspase-3 activation Control (C/C), antioxidant (C/A) , enrichment (C/E) combination (E/A)
Immunofluorescent staining for cleaved caspase-3 and cleaved product (fractin) in the canine frontal cortex.
Caspase 3 Fractin Combined
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Combined EE+AOX increases BDNF mRNA, and counteracts BDNF decline with age
control EE AOX EE+AOX Aged Aged EE+AOX
Young
(Fahnestock, Cotman, et al., 2010)
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How do the treatments affect Beta-amyloid?
• Levels decreased? • Or maybe increased tolerance?
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Combined EE+AOX decreases beta-amyloid plaque load.
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Change in Amyloid load does not correlate with behavioral improvement
Pearson correlation p value
Spatial Memory Performance 0.198 n.s
Black/white discrimination errors -0.096 n.s
Black/white reversal errors -0.134 n.s
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Enrichment, Aox treatment: minimally reduce AB42
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Hypothesis for synergistic effectiveness of the combined EE + AOX treatment
• AOX intervention improves mitochondrial function: – may “enable” enrichment stimuli to better engage plasticity
and protective mechanisms
• Combined EE+AOX results in greater learning improvements, pathology reduction, and BDNF induction than either EE or AOX alone
• Brain tolerates β-amyloid
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Role of BDNF/Exercise on Enabling Cognitive Performance
• Can BDNF/exercise enable learning of normally sub-threshold events? – Test with Object Location Memory Task, an
example of hippocampal-dependent “incidental” learning
• How critical is exercise-induction of BDNF in hippocampus for enabling learning?
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
3min Train 24h Test Habituate Handle
Sed v Ex Day
5min
Exercise mice 3 wks, expose to sub-threshold training for object location memory and determine if mice now learn and retain experience 24hrs
sac
Subthreshold training time
Retention Test
24h Retention Test Performance
(Stefanko et al. 2009)
Sub-threshold training (3 min): animal cannot discriminate between familiar and novel object location
10 min 3 min No habituation
Training duration
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
3min Train 24h Test Habituate Handle
Sed v Ex
Day
5min
Exercise enables sub-threshold learning The effectis equivalent to Sodium Butyrate (NaB) –
a histone deacetylase inhibitor sac
Sub-threshold OLM performance (long term memory)
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3min 4d
Sed v Ex
5min
siRNA surgery
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
sac
BDNF is required for Exercise to enable sub-threshold learning
Blocking exercise induction of BDNF with siRNA prevents discrimination of the novel location
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Does MCI engage Molecular Reserve ?
• Is MCI mild AD? • Are compensatory molecular
mechanisms engaged in the MCI brain? • Evaluate with microarray analyses
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Microarray study: MCI, AD, normal aged
• Well powered microarray study (63 cases, see below) • 4 brain regions
– EC, HC, Superior Frontal Gyrus (SFG) – Somatosensory gyrus (PCG) – “control region”
• Affymetrix (HgU133 plus 2.0 chips)
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MCI cases cluster closely
Black: MCI Red: AD Green: Aged Control
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Electron transport genes: extensive upregulation across brain in MCI
Red= downregulated Green = upregulated
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Energy and synaptic genes: Downregulated in AD, but Upregulated in MCI
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MCI brain mobilizes mechanisms to increase anabolic + metabolic function
• Upregulation of Protein biosynthesis/trafficking/ turnover • Synaptic genes mobilized
– Neurotransmitter release machinery (SNAREs) – Neurotransmitter receptors (Glu, GABA, Ach) – Synaptic structure and stabilization genes
• Upregulation of Mitochondrial energy generation • Molecular mobilization in MCI brain, likely serving to support
cognitive reserve (ultimately fails with decline to AD)
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Summary • Brain mobilizes many diverse mechanisms to
maintain function in the wake of age and pathology build up.
• Environmental enrichment, exercise, and cognitive training enhance molecular counteractive strategies
• Even in MCI the molecular machinery is engaged to counteract decline
• Cognitive reserve may be integrated brain plasticity
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Nicole Berchtold, Ph.D. Liz Head, Ph.D Bill Milgram, Ph.D. Viorela Pop, Ph.D. Michael Valenzula, Ph.D. Joyce Siete, Ph.D. Dan Gillen, Ph.D. Karlie Intlekofer, Ph.D. Marcel Wood, Ph.D. Patrick Sullivan, Ph.D. Alan Butterfield, Ph.D. M. Fahnestock, Ph.D David Bennett,Ph,.D. Marwan Sabbagh, MD. Tom Beach, MD. Christina de Rivera Frank LaFerla, Ph.D. and UCI ADRC
Acknowledgements
Funding provided by NIA
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MCI: Gene expression is not intermediate between Aged and AD profiles