Growth Factor (GF) Cascades and exercise and the regulation of

cognition, mood and motor control:

Are GFs a common mechanism? Carl W. Cotman

Director, Institute of Brain Aging

University of California, Irivne

Outline

• Part I. Exercise regulates learning, neurogenesis and angiogenesis via growth factor cascades

• Part II. Exercise improves learning and reduces β-amyloid accumulation and inflammation in Alzheimer mouse models

• Part III. Environmental enrichment antioxidant diet improve learning in aged canines

Exercise induces growth factor cascades and regulates peripheral risk factors for brain dysfunction

BDNF (Brain Derived Neurotrophic Factor) is necessary for learning:

BDNF – Brain Derived Neurotrophic Factor, “Brain Fertilizer”

• Necessary for learning and long term synaptic change

• Stimulates synaptic growth and neurogenesis• Linked to “depression” in rodents• Protects neurons from injury including those in

motor systems

How to get more?• Exercise?

Is BDNF increased with exercise in brain?

Exercise increases BDNF mRNAHIPPOCAMPUS:

Rats: 1 week exercise (male sprague-dawley, 3 months)

Berchtold et al., 2002

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Exercising

* p < 0.05

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*

Exercise Enhances Learning in the Morris Water Maze

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)

Take home:

• Thus exercise improves the state of readiness of learning, faster and lower threshold, including theta long term potentiation, a synaptic analogue of learning.

Practical Questions

• How long lasting is the increase in BDNF after stopping exercise? 2wks

• How frequent is necessary? 3-4X/wk

• Can the increase be recovered rapidly if exercise is stopped for a period? Yes, if within 2wks

Other targets of exercise

Neurogenesis, Angiogenesis

Neurogenesis

• Occurs in select brain regions, e.g., hippocampal dentate gyrus

• Correlates with improved learning; new cells have a low threshold for synaptic transmission

• A mechanism in antidepressant action • Linked to IGF-1 and BDNF• Increases with running and is sustained with age

but at reduced levels (van Praag, 2005; Kronenberg, 2005)

(van Praag, 2005)

Neurogenesis in the young and aged dentate gyrus.

New neurons?

• Exercise can increase brain vessels and the generation of new neurons in brain.

• Humans?

Pereira et al., 2007

Exercise selectively increases dentate gyrus cerebral blood volume in mice.

Pereira et al., 2007

Exercise-induced increases cerebral blood volume and correlates with neurogenesis in mouse

hippocampus

Pereira et al., 2007

Exercise increases cerebral blood volume (CBV) in human hippocampus. Exercise had a selective effect on dentate gyrus CBV. Before exercise (open bars) and after exercise (filled bars).

Growth factor cascades regulate learning, neurogenesis, and angiogenesis (Cotman,2007, Trends in

NS).

Effects of exercise on normal aging

Behavior Neuroanatomy Cellular/molecular References

Human Improves learning & memory, slows cognitive decline, risk for dementia

Reduces brain atrophy, prevents decline in cerebral blood flow, increases bloodflow (neurogenesis?)

Needs investigation Rogers et al. 1990; Hill, et al. 1993; Laurin et al. 2001; Yaff e et al. 2001; Colcombe et al. 2003; Weuve et al. 2004; Rovio et al. 2005; Colcombe et al. 2006; Larson et al. 2006; Pereira et al., 2007

Animal Improves learning & memory, slows cognitive decline

Slows decline in neurogenesis, lowers threshold for LTP induction, increases angiogenesis

BDNF, prevents decline in precursor cell activity in dentate gyrus

Farmer et al. 2004; Adlard et al. 2005; van Praag et al. 2005; Ding et al. 2006; Kronenberg et al. 2006

Part II: Is exercise an effective intervention in Alzheimer’s disease

transgenic mouse models ?

• Will voluntary running improve learning and memory?

• Reduce β-amyloid in the brain?

• Stimulate neurogenesis?

Animal model

• Widespread plaque deposition, including the hippocampus andcortex

Chishti et al., JBC 276: 21562-21570, 2001.

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

Exercise improves the performance of TgCRND8 animals in the Morris water maze

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Day 1 Day 2 Day 3 Day 4 Day 5 Day 6

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Long-term running reduces ß-amyloid load in TgCRND8 animals

(by immunohistochemistry)

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Aß1-40 Aß1-42For

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Long-term running reduces ß-amyloid in TgCRND8 animals (by ELISA)

Long-term running enhances neurogenesis in TgCRND8 animals

Can exercise improve learning in late stage AD?

???????????

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Pre- fibrilar β-amyloid is decreased by 3 wks running in 18m old

Tg2576 miceC

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Inflammation

• Is a common component of the metabolic syndrome

• IL-1 and TNF impair insulin/IGF-1 signaling (insulin resistance) and increase the risk for progression (various refs)

• IL-1 impairs BDNF and neurotrophin signaling (“neurotrophin resistance”) (Tong, 2007)

• Can exercise reduce inflammation????

IL-1IL-1 0

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IFN-IFN-

Exercise reverses the effects of Exercise reverses the effects of “AD” on inflammatory system“AD” on inflammatory system

Pro-inflammatory: BAD Anti-inflammatory: GOOD

Inflammation

• Impairs insulin/IGF-1 signaling, e.g., IL-1β, TGFα (insulin resistance)

• Impairs BDNF signaling, e.g., IL-1β (neurotrophin resistance)

• Exercise thus acts via growth factor cascades at multiple levels. Induction and relief from suppression.

BDNF signal transduction: IL-1β impairs IRS coupling similar to its effect on IGF-1

BDNF

• BDNF and mood (Martinowich, etal, Nature Neuroscience, 2007)

• Hipocampal neurogenesis in depression (Sahay and Hen, Nature Neuroscience 2007)

Part III: Environmental enrichment/exercise and Diet: multi-factorial interventions

• Supplements/Nutrients

• Some dietary factors may regulate brain health and cognitive performance

• Interact with environmental enrichment and exercise

• Can control the metabolic syndrome

Can antioxidants and/or Exercise/Environmental Enrichment

Delay the Development of Age Dependent Cognitive Dysfunction and Neuropathology in Canines?

Spatial Memory and Treatment

Year of Study

Year 1 Year 2 Year 3

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P<.09

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Cognition, Mood and Motor control?

• Growth factor cascades and their regulation underlie aspects of enhancing brain function and structure and protecting from pathology (Cotman, 2007, Trends in NS)

• Growth factor signaling can be impaired by inflammation

• Growth factor cascades may be a common denominator for cognitive impairment, depression and some aspects of motor control??

• Exercise accesses these mechanisms

Acknowledgments

• Nicole Berchtold

• Liz Head

• Paul Adlard

• Liqi Tong

• Robert Balazs

• Kate Nicole

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

Enrichment Protocol

• Play toys• Kennelmate• 3x20 min walks• Additional cognitive

experience

Controls

6 months

Effect of diet on oddity discrimination in aged beagles

Oddity task

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Diet fortified animals make few mistakes as task difficulty increases

Effect of diet on oddity discrimination in aged beagles

Is the intervention able to “reverse” age related

cognitive dysfunction?

Summary

• Part I: Exercise access brain learning mechanisms and regulates growth factors

• Part II: Exercise can delay onset of age-related pathology and improve learning even once pathology has evolved

• Part III: Exercise and environmental enrichment with an antioxidant diet can improve learning