Isoflurane and Alzheimer’s 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

Isoflurane and Alzheimer’s Disease Neuropathogenesis

Isoflurane and Alzheimer’s Disease Neuropathogenesis

Alzheimer’s 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 Alzheimer’s disease (AD).

(Reviewed in Xie and Tanzi, 2006)

QuickTime™ and aTIFF (LZW) decompressor

are needed to see this picture.

(Xie et al., 2006a)

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., 2006b)

Isoflurane-induced caspase-3 activation in H4-APP cells is dose-dependent



(Xie et al., 2007)

Isoflurane induces caspase-3 activation without detectable changes in APP processing

and A generation in naïve H4 cells



(Xie et al., 2007)



Z-VAD attenuates the isoflurane effects on caspase-3 activation, APP processing and A levels

(Xie et al., 2007)

Isoflurane enhance levels of BACE and -secretase



(Xie et al., 2007)



iA5 and clioquinol attenuate the isoflurane-induced caspase-3 activation

(Xie et al., 2007)

A potentiates the isoflurane-induced caspase-3 activation



(Xie et al., 2007)

Summary



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.

Conclusion

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.

Future direction

Rudolph E. Tanzi, Ph.D.Yuanlin Dong, M.D., M.S.Uta MaedaRob 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 CareMassachusetts General Hospital and Harvard Medical School****************************************************************************Deborah J. Culley, M.D.Gregory Crosby, M.D.Department of Anesthesia,Brigham & Women’s 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. NIH K12 (AG 000294-17), K08 (NS048140-01), P60 (AG008812-15) and Jahnigen award from

American Geriatrics Society to Zhongcong Xie

Acknowledgements

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Isoflurane and Alzheimer’s Disease Neuropathogenesis