1. 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

2. 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

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

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

5. 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?

6. Is BDNF increased with exercise in brain?

7. Exercise increases BDNF mRNA HIPPOCAMPUS: Rats: 1 week exercise (male sprague-dawley, 3 months) Berchtold et al., 2002

8. Exercise Enhances Learning in the Morris Water Maze

9. 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)

10. 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.

11. 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

12. Other targets of exercise Neurogenesis, Angiogenesis

13. 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)

14. (van Praag, 2005) Neurogenesis in the young and aged dentate gyrus.

15. New neurons? Exercise can increase brain vessels and the generation of new neurons in brain. Humans?

16. Pereira et al., 2007 Exercise selectively increases dentate gyrus cerebral blood volume in mice.

17. Pereira et al., 2007 Exercise-induced increases cerebral blood volume and correlates with neurogenesis in mouse hippocampus

18. 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).

19. Growth factor cascades regulate learning, neurogenesis, and angiogenesis (Cotman,2007, Trends in NS).

21. Part II: Is exercise an effective intervention in Alzheimers disease transgenic mouse models ? Will voluntary running improve learning and memory? Reduce β-amyloid in the brain? Stimulate neurogenesis?

22. Animal model Widespread plaque deposition, including the hippocampus and cortex Chishti et al., JBC 276: 21562-21570, 2001.

23. 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

24. Exercise improves the performance of TgCRND8 animals in the Morris water maze Average escape latency (seconds) ± standard error * * * * p<0.02

25. Long-term running reduces ß-amyloid load in TgCRND8 animals (by immunohistochemistry)

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

27. Long-term running enhances neurogenesis in TgCRND8 animals

28. Can exercise improve learning in late stage AD? ???????????

29. Reference memory improves in Tg2576 run * * *

30. Pre- fibrilar β-amyloid is decreased by 3 wks running in 18m old Tg2576 mice

31. 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????

32. IL-1 IL-1 IFN- IFN- Exercise reverses the effects of AD on inflammatory system Pro-inflammatory: BADAnti-inflammatory: GOOD

33. 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.

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

35. BDNF BDNF and mood (Martinowich, etal, Nature Neuroscience, 2007) Hipocampal neurogenesis in depression (Sahay and Hen, Nature Neuroscience 2007)

36. 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

37. Can antioxidants and/or Exercise/Environmental Enrichment Delay the Development of Age Dependent Cognitive Dysfunction and Neuropathology in Canines?

38. Spatial Memory and Treatment P<.09 P<.05

39. 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

40. Acknowledgments Nicole Berchtold Liz Head Paul Adlard Liqi Tong Robert Balazs Kate Nicole

41. 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

42. Enrichment Protocol Play toys Kennelmate 3x20 min walks Additional cognitive experience Controls

43. 6 months

44. Diet fortified animals make few mistakes as task difficulty increases Effect of diet on oddity discrimination in aged beagles

45. Is the intervention able to reverse age related cognitive dysfunction?

46. 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