The Glymphatic System – A New Player in Alzheimer Disease?

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

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  • Astrocytes areelectrically non-excitable and have traditionally been regarded as the supportive cell of the brain. The glia field has made tremendous progress over the past decade and we have developed a much more sophisticated view on the multi-faceted function of astrocytes that is so than just 15 years. We know know that astrocytes can mudulatesynapric transmission and play important role in complex cognitive functions such as working memory and sleep – with several of the key studies done here at Penn. One concern is that essential the new data on organization, development, differentiation, and function have been generated in rodent. Even worse, essentially all our understanding of astrocytic calcium signaling and gliotransmissionhas been collected in mice or rat pups.
  • The influx of tracer can also be studied by injecting the tracer in CM follwoe by perfusion of the brain at various time points thereafter. We have here injected a small red tracer anda larger green tracer and harvested the brain just 5 min later. Most of the larger penetrating arteries are otline and it is clear that the red smaller tracer
  • The influx of tracer can also be studied by injecting the tracer in CM follwoe by perfusion of the brain at various time points thereafter. We have here injected a small red tracer anda larger green tracer and harvested the brain just 5 min later. Most of the larger penetrating arteries are otline and it is clear that the red smaller tracer
  • The influx of tracer can also be studied by injecting the tracer in CM follwoe by perfusion of the brain at various time points thereafter. We have here injected a small red tracer anda larger green tracer and harvested the brain just 5 min later. Most of the larger penetrating arteries are otline and it is clear that the red smaller tracer
  • The influx of tracer can also be studied by injecting the tracer in CM follwoe by perfusion of the brain at various time points thereafter. We have here injected a small red tracer anda larger green tracer and harvested the brain just 5 min later. Most of the larger penetrating arteries are otline and it is clear that the red smaller tracer
  • Despite decades of effort, one of the biggest mysteries in biology is still why sleep is restorative and conversely why lack of sleep impairs brain functions
  • 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

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