Isoflurane and Alzheimer

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Isoflurane and Alzheimers Disease
Neuropathogenesis
Zhongcong Xie, M.D., Ph.D. Genetics and Aging
Research Unit MassGeneral Institute for
Neurodegenerative Disease Department of
Neurology Department of Anesthesia and Critical
Care Massachusetts General Hospital Harvard
Medical School Boston, Massachusetts
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• Alzheimers disease (AD) is one of the greatest
  public health problems in the US and in the
  world, and its impact will only increase with
  demographic changes anticipated in the coming
  decades.
• Currently, AD affects 4.5 millions Americans. It
  it estimated that the number of AD patients will
  reach 13.2 millions in the US by 2050, if no
  treatments are found.
• A? production/accumulation is the important part
  of the AD neuropathogenesis.
• Increasing evidence also suggests a role for
  caspase activation and apoptosis in AD
  neuropathogenesis.
• An estimated 100 million patients worldwide have
  surgery each year. Several reports have suggested
  that anesthesia and surgery may facilitate the
  development of Alzheimers disease (AD).

(Reviewed in Xie and Tanzi, 2006)
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Isoflurane induces caspase-3 activation, reduces
cell viability and increases A? generation in H4
human neuroglioma cells overexpressing APP
(H4-APP cells)
(Xie et al., 2006a)
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Isoflurane-induced caspase-3 activation in
H4-APP cells is dose-dependent

(Xie et al., 2006b)
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Isoflurane induces caspase-3 activation without
detectable changes in APP processing and A?
generation in naïve H4 cells

(Xie et al., 2007)
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Z-VAD attenuates the isoflurane effects on
caspase-3 activation, APP processing and A?
levels

(Xie et al., 2007)
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Isoflurane enhance levels of BACE and ?-secretase

(Xie et al., 2007)
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iA?5 and clioquinol attenuate the
isoflurane-induced caspase-3 activation

(Xie et al., 2007)
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A? potentiates the isoflurane-induced caspase-3
activation

(Xie et al., 2007)
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Summary

(Xie et al., 2007)
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Conclusion

• Acute perioperative insults, e.g., hypoxia,
  hypocapnia and anesthetics, may affect A?
  metabolism and apoptosis, thereby increasing the
  risk of developing AD.
• Isoflurane induces a vicious cycle of apoptosis
  and A? generation.
• Isoflurane may induce apoptosis via A?
  oligomerization/fibrillar aggregation.

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Future direction

• Systematically assess the effects of isoflurane
  on apoptosis, APP processing, A? generation,
  amyloid amount/disposition, regulation of gene
  expression in both mice and humans.
• Further determine the molecular mechanisms by
  which isoflurane induces apoptosis, affects APP
  processing and increases A? accumulation.

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Acknowledgements

• Rudolph E. Tanzi, Ph.D.
• Yuanlin Dong, M.D., M.S.
• Uta Maeda
• Rob Moir, Ph.D.
• Guohua Zhang, M.D., Ph.D.
• Bin Zhang, M.D.
• Genetics and Aging Research Unit, Department of
  Neurology,
• Department of Anesthesia and Critical Care
• Massachusetts General Hospital and Harvard
  Medical School
• 
  
• Deborah J. Culley, M.D.
• Gregory Crosby, M.D.
• Department of Anesthesia,
• Brigham Womens Hospital and Harvard Medical
  School
• 
  
• Weiming Xia, Ph.D.
• Center for Neurological Diseases, Harvard
  Institute of Medicine and Harvard Medical School
• 
  
• NIH MH 60009-02 and AG 014713-07 to Rudy Tanzi.