Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

The Glymphatic System – A New Player in Alzheimer Disease?

9,936 views

Published on

Presentation made January 8, 2014 at the AlzForum live webinar: http://www.alzforum.org/webinars/neurovascular-underpinnings-alzheimers-dementia-0

Published in: Health & Medicine
  • Be the first to comment

The Glymphatic System – A New Player in Alzheimer Disease?

  1. 1. The Glymphatic System – A New Player in Alzheimer Disease? Maiken Nedergaard Univ. of Rochester
  2. 2. CNS is a metabolic highly active organ
  3. 3. CNS is a metabolic highly active organ • ~ 2% of the body weight (3 pounds)
  4. 4. CNS is a metabolic highly active organ • ~ 2% of the body weight (3 pounds) • ~ 15% of the cardiac output • ~ 20% of total body O2 consumption • ~ 25% of total body glucose consumption
  5. 5. CNS is a metabolic highly active organ • ~ 2% of the body weight (3 pounds) • ~ 15% of the cardiac output • ~ 20% of total body O2 consumption • ~ 25% of total body glucose consumption All biological activity is associated with production of waste products
  6. 6. CNS is a metabolic highly active organ • ~ 2% of the body weight (3 pounds) • ~ 15% of the cardiac output • ~ 20% of total body O2 consumption • ~ 25% of total body glucose consumption All biological activity is associated with production of waste products
  7. 7. CNS is a metabolic highly active organ • ~ 2% of the body weight (3 pounds) • ~ 15% of the cardiac output • ~ 20% of total body O2 consumption • ~ 25% of total body glucose consumption All biological activity is associated with production of waste products Does the brain really recycle all cellular waste products?
  8. 8. CNS is lacking a lymphatic system
  9. 9. CNS is lacking a lymphatic system elephantiasis
  10. 10. CSF has been proposed to act as a sink for waste B/Y?
  11. 11. CSF has been proposed to act as a sink for waste Waste diffusion? B/Y?
  12. 12. Pulsatility may drive CSF into brain CSF pulsation B/Y?
  13. 13. In vivo imaging of CSF tracers
  14. 14. In vivo imaging of CSF tracers Vasculature CSF tracer 180 µm below the surface
  15. 15. Ex vivo imaging of CSF tracers Texasred dextran FITC dextran 5 min
  16. 16. Ex vivo imaging of CSF tracers Texasred dextran FITC dextran 5 min
  17. 17. CSF tracers rapidly enter brain along the vasculature Texasred dextran FITC dextran 5 min 5 min
  18. 18. CSF tracers rapidly enter brain along the vasculature Astrocytic Vascular Endfeet AQP4 GFAP DAPI
  19. 19. Does AQP4Brain AquaporinsCSF influx? promote Brain Bulk Flow Astrocytic Vascular Endfeet Wild Type AQP4 GFAP DAPI Tracer DAPI 30 min
  20. 20. Does AQP4Brain AquaporinsCSF influx? promote Brain Bulk Flow AQP4 KO Astrocytic Vascular Endfeet Wild Type AQP4 GFAP DAPI Tracer DAPI 30 min
  21. 21. Novel macroscopic clearance path in CNS Science, 2013
  22. 22. Glymphatic system Jeff Iliff, 2012
  23. 23. Brain Bulk Flow Does AQP4Brain Aquaporins in amyloid clearance? play a role
  24. 24. Brain Bulk Flow Does AQP4Brain Aquaporins in amyloid clearance? play a role 125IAmyloid 1-40
  25. 25. Brain Bulk Flow Does AQP4Brain Aquaporins in amyloid clearance? play a role 125IAmyloid 1-40
  26. 26. Brain Bulk Flow AQP4 deletionAquaporins amyloid clearance Brain reduces 125IAmyloid 1-40
  27. 27. Diagnostic test of glymphatic function based on MRI JCI, 2013
  28. 28. Diagnostic test of glymphatic function based on MRI When is the glymphatic most active? JCI, 2013
  29. 29. Does arousal regulate glymphatic activity?
  30. 30. Does arousal regulate glymphatic activity?
  31. 31. Does arousal regulate glymphatic activity?
  32. 32. Does arousal regulate glymphatic activity?
  33. 33. In vivo imaging of tracer influx in the awake state Cascade blue IV CSF tracer
  34. 34. In vivo imaging of tracer influx in K/X anesthesia Cascade blue IV CSF tracer
  35. 35. In vivo imaging of tracer influx in sleep vs awake CSF tracer CSF tracer
  36. 36. In vivo imaging of tracer influx in awake vs K/X anesthesia 200 µm 200 µm 200 µm CSF tracer - awake CSF tracer - anesthesia
  37. 37. In vivo imaging of tracer influx in sleep vs awake C S F 200 µm 200 µm 200 µm t r a c eCSF tracer - awake r CSF tracer - sleep
  38. 38. In vivo imaging of tracer influx in sleep vs awake vs anesthesia
  39. 39. In vivo imaging of tracer influx in awake vs following exposure to norepinephrine receptor antagonists
  40. 40. In vivo imaging of tracer influx in awake and following exposure to norepinephrine receptor antagonists 200 µm 200 µm 200 µm
  41. 41. In vivo imaging of tracer influx in awake and following exposure to norepinephrine receptor antagonists 200 µm 200 µm 200 µm
  42. 42. In vivo imaging of tracer influx in awake and following exposure to norepinephrine receptor antagonists 200 µm 200 µm 200 µm
  43. 43. Is glymphatic clearance reduced in the awake state?
  44. 44. Glymphatic clearance is reduced in the awake state Amyloid *; p<0.01, awake compared with sleep and KX, n = 77
  45. 45. Diseases associated with sleep disorders • • • • Alzheimer's disease (AD) Parkinson's disease (PD) Huntington's disease Progressive supranuclear palsy • • • • Hydrocephalus Encephalitis Multiple sclerosis Traumatic and ischemic injury
  46. 46. Conclusion: •The glymphatic system share many functions with the system lymphatic system •AQP4 deletion suppress clearance of beta-amyloid by 60% •Glymphatic clearance peaks during sleep or anesthesia, when norepinephrine is low Implications: •Macroscopic glymphatic clearance may play a role in neurodegenerative diseases. Is AQP4 a new therapeutic target? •Sleep promotes removal of biological waste in CNS •Glymphatic influx of CSF can also be used to deliver drugs to CNS
  47. 47. Jeff Iliff Lulu Xie Minghuan Wang Ditte Lovatt Nathan Smith Karl Kasischke Hongyi Kang Nancy Oberheim Martha Windrem Xioaning Han Takahiro Takano Lane Bekar Arnulfo Torres Qiwu Xu Marisa Cotrina Marie Simard Xiaohai Wang Jane Lin Guofeng Tian Nanhong Liu NINDS/NIH, Dana Foundation, Adelson, Keck Foundation, Mathers Foundation and NY State Collaborators: Helene Benveniste Alcino Silva Charles Nicholson Gerald Dienel Jian Kang Klaus Willecke Bruce Ransom Steve Goldman

×