Neurovascular Regulation in Health and 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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Neurovascular Regulation in Health and Disease

  1. 1. Neurovascular Regulation in Health and Disease Costantino Iadecola, M.D. Brain and Mind Research Institute Weill Cornell Medical College New York, NY, USA
  2. 2. Brain vascularization and the neurovascular unit Nat Neurosci Rev 5: 347, 2004
  3. 3. Mechanisms of Cerebrovascular Regulation FUNCTIONAL HYPEREMIA SYNAPTIC ACTIVITY ASTROCYTE TIGHT JUNCTION END-FEET MYOCYTE/PERI CYTE FUNCTIONAL ENDOTHELIAL CELL IMAGING AUTOREGULATION CHANGE IN CBF +50 AUTOREGULATED RANGE 0 -50 50 100 150 MEAN ARTERIAL PRESSURE (MMHG) fMRI BOLD
  4. 4. Multiple agents and cells mediate the increase in CBF evoked by activation Synaptic activity Ca++ NOS COX-2 Glu GJ mGluR ATP Ado Glu K+ H+ NO, PGs Ado Ca++ waves Ca++ Central pathways Interneurons Ca++ PGs COX EETs P450 Astrocytes ATP Ado K+ siphoning Arteriole NO GABA 5HT NE ACh DA SP NT VIP SOM NPY Brain Lang 102: 141-152, 2007
  5. 5. The Neurovascular Unit: Beyond Blood Flow Regulation Myocyte/PericyteAging Endothelium Cerebral Arteriole Perivascular cells Hypertension •• •• • Astrocyte •• • Alzheimer Neuron Flow regulation BBB exchange Axon Immune surveillance Trophic support (vascular niche) Acta Neuropathol 120:287, 2010
  6. 6. Do Cerebrovascular Factors Contribute to Alzheimer’s Disease? 1. Cerebral blood flow is reduced in presymptomatic individuals at genetic risk for AD, cerebral blood vessels are not normal; 2. AD and cerebrovascular diseases share similar risk factors (hypertension, dyslipidemia, obesity, etc.); 3. Small ischemic lesions aggravate the dementia in patients with mild AD pathology (The Nun Study). Nat Rev Neurosci. 5:347, 2004
  7. 7. Do vascular factors contribute to the mechanisms of Alzheimer’s disease? A peptides ? Neuronal dysfunction Vascular dysfunction Cell. Mol. Neurobiol, 23:681, 2003
  8. 8. Methods to investigate neurovascular regulation in mice Ringer or Acetylcholine Neocortex 100 MAP mmHg Field potentials CBF CBF % incr. 60 CP 130 Thal 100 Stim. Functional hyperemia, endothelium-dependent vasodilatation (acetylcholine, A23187), smooth muscle function (adenosine)
  9. 9. Neural and vascular CBF responses are attenuated in Tg2576 mice at an early age APP mice (age 3 months) Wild Type 100 * p<0.05; n=5/group 30 20 * * 10 0 150 APP mice CBF (% change) CBF (% increase) 40 Wild type APP mice 50 0 -50 Whisker Stimulation Acetylcholine -100 0 50 100 150 Mean arterial pressure (mmHg) Nat Neurosci 2:157,1999; PNAS 97:9735, 2000 Smooth muscle function not affected 200 AJP 2002; 283:H315
  10. 10. Vascular dysregulation increases the susceptibility to ischemic injury in Tg2576 mice Intraischemic CBF Infarct volume Time after MCA occlusion (min) *Resting flow: Non-Tg: 148±1; Tg: 105±9 ml/100g/min J. Neurosci 76:1755, 1997
  11. 11. AD patients have more strokes than age-matched controls
  12. 12. NADPH oxidase is a major source of free radicals in cerebral blood vessels in AD models Tg2576 mice Ligand 3-NT NADPH oxidase NOX p22 R Serine phosphorylation p47 Rac1 p67 O2-• Cellular dysfunction JCBFM 24:334, 2004 PKC
  13. 13. Developing APP mice deficient in NOX2 Tg2576 Tg2576 X NOX2-/- Tg2576/NOX2-/-
  14. 14. Nox2 deficiency rescues neurovascular dysfunction and behavioral deficits in Tg2576 mice Old (12-15 months) Nox2-/WT 10 0 10 0 Tg2576 * * # 10 # * # * 25 0WT 0 100 50 0 Adenosine Adenosine 30 Tg2576/Nox2-/- 20 10 50 0 Tg2576 WT Nox2-/- Nox2-/Tg2576 Tg2576/Nox2-/- WT Nox2-/-WT Nox2-/- Tg2576 Tg2576/Nox2-/Tg2576 Tg2576/Nox2-/- Tg2576/Nox2-/- D 40 30 (DHE) * # B 150 100 * * D 40 ROS * * B 150 Time in novel arm (sec) 25 20 50 Tg2576/Nox2-/Tg2576 Tg2576/Nox2-/WT Bradykinin Bradykinin 20 * Tg2576 Nox2-/- 50 75 Acetylcholine CognitiveAcetylcholine function Time in novel arm (sec) # CBF (% increase) * 20 CBF (% increase) 0 CBF (% increase) WT C 30 10 * 10 C 30 20 * # CBF (% increase) 0 * 75 CBF (% increase) 10 20 Novel arm entry (%) CBF (% increase) 20 CBF (% increase) Whisker stimulation 100B 30 100 30 Whisker stimulation A B A A 30Whisker stimulation Novel arm entry (%) A 30 CBF (% increase) Young (3-4 months) 20 PNAS 105: 1347, 2008 10 WT Nox2
  15. 15. CD36, an innate immunity receptor, binds A and activates inflammatory signaling CD36 A NOX Lipid raft Nucleus Serine phosphorylation p47 Vav-GEF NF-κB NADPH oxidase p22 Rac1 p67 • O2- inflammation Oxidative stress
  16. 16. Deletion of CD36 prevents the neurovascular dysfunction and oxidative stress in Tg2576 mice Tg2576 Tg2576 X CD36-/- Radicals Tg2576/CD36-/- PNAS 108: 5063, 2011
  17. 17. CD36 deletion reduces cerebral amyloid angiopathy, but not amyloid plaques No difference in plaque load or microglial density PNAS 110: 3089, 2013
  18. 18. Treatment of vascular risk factors slows down the progression of dementia in patients with AD Deschaintre et al., Neurology 73: 674, 2009
  19. 19. The neurovascular unit in health and disease Hypertension Alzheimer’s disease Aging USC Health Perivascular cell Neurovascular dysfunction •Oxidative stress Cerebral Arteriole Neuron • •• •• ••• Cognitive impairment Astrocyte •Inflammation

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