Assistant Professor
Ph.D., The University of British Columbia, Vancouver, B.C., Canada, 1993
Max Planck Institute for Psychiatry, Munich, Germany, 1993-96
The Scripps Research Institute, La Jolla, CA, 1996-97
The Burnham Institute, La Jolla, 1997-99
La Jolla Institute for Allergy and Immunology, 1999-2001

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Research Summary

My lab is interested in how brain cells die in disorders such as Alzheimer's disease, stroke, diabetic neuropathy, and Multiple Sclerosis. All cells in our bodies are capable of triggering a kind of cellular suicide, called apoptosis. This kind of proactive cell death is very important in eliminating damaged, pre-cancerous, infected, superfluous, or otherwise unwanted cells from the body. However, inappropriate activation of apoptosis in brain cells can eliminate important neurons and lead to clinical deficits. It has been suggested that most neurodegenerative disorders result from such inappropriate apoptosis. We are investigating how apoptotic cell death is activated and controlled in neurons and other brain cells, as it relates to the disorders detailed above. For example, we have found that an apoptotic trigger thought to be used exclusively by the immune system, may in fact be responsible for the progression of Alzheimer's disease. The amyloid plaques that develop in Alzheimer's brain may be interpreted as a breach of the blood brain barrier by neurons in the local area. The neurons respond to this breach by producing large amounts of Fas ligand, perhaps to limit the immune system from damaging them. This high amount of Fas ligand will kill many of the immune cells that come into the area and so suppress any possible immune response to the amyloid plaques. Further, the high amounts of Fas ligand may directly kill the neurons themselves. Conversely, too little Fas ligand may be just as bad by allowing the immune system too much access to the brain and spinal cord. In this instance the immune system may create immune responses to viable brain cells as happens in Multiple Sclerosis. In addition to studying Fas ligand as a regulator of immune access to the CNS, we are also studying the activation of neuron apoptosis in stroke and diabetes.









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Figure legend: A schematic representation of mechanisms involved in Alzheimer's disease (not to scale). At the top left a large pyramidal neuron in the hippocampus makes beta-amyloid by sequential cleavage of amyloid precursor protein (APP) by Beta-amyloid cleaving enzyme (BACE) and then gamma-secretase. Single monomers of beta-amyloid are made throughout life, but their levels are elevated in the brains of Alzheimer's patients. This higher concentration predisposes the beta-amyloid single monomers to form aggregates or oligomers, and eventually plaques (green cluster below the red neuron. The green image is a from a microscope photo of a real plaque that developed in our mouse model for Alzheimer's disease. Beta-amyloid aggregates can also directly kill neurons (right middle) by triggering a cell suicide process called, apoptosis. Usually beta-amyloid monomers and oligomers are removed from the brain through the blood stream. However, in Alzheimer's disease beta-amyloid can also for aggregates in the space between two cell layers in the larger blood vessels (arterioles), shown on the far right, called cerebral amyloid angiopathy or CAA. The formation of CAA can also be precipitated by atherosclerosis depicted by the white clump. The aggregates of CAA continue to grow and actually squeeze the blood vessel, restricting blood flow and making patients more susceptible to blood clots and other causes of blockage. Lower blood flow or blockage in these vessels results in those parts of the brain receiving less oxygen than they normally should, referred to as hypoxia. Neurons are very sensitive to hypoxia even when it happens for hours or minutes, and they will respond by dying by apoptosis or necrosis, through a mechanisms that relies on glutamate excitotoxicity of NMDA receptors. The new drug memantine blocks some of this death, but it does not impact the factors leading up to this condition, or improve the underlying pathology. However, preventing this kind of cell death can significantly slow down Alzheimer's progression.

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Publications

Ethell, D.W. and Fei, Q.  Parkinson's-linked genes and toxins that impact neuronal cell death through the Bcl-2 family.  Antioxidants & Redox Signaling [Epub ahead Aug 20, 2008].

Lin, K.-T., Sloniowski, S., Ethell, D.W. and Ethell, I.M.  Ephrin-B2 induced cleavage of EphB2 receptor is mediated by matrix metalloproteinases to trigger cell repulsion. J. Biol. Chem [Epub ahead Aug 19, 2008].

Fei, Q. and Ethell, D.W.  Maneb potentiates paraquat neurotoxicity by inducing key Bcl-2 family members.  J. Neurochem., Feb. 8, 2008 [Epub ahead).

Oppenheim, R.W., Blomgren, K., Ethell, D.W., Koike, M., Komatsu, M., Prevette, D., Roth, K.A., Uchiyama, Y., Visant, S. and Zhu, C.  Developing post-mitotic mammalian neurons in vivo lacking Apaf-1 undergo programmed cell death by a caspase-independent, nonapoptotic pathway involving autophagy.  J. Neurosci. 28: 1490-1497, 2008.

Fei, Q., McCormack, A.L., Di Monte, D.A. and Ethell, D.W.  Paraquat neurotoxicity is mediated by BNip3 and Noxa activation of Bak.  J. Biol. Chem. 283: 3357-3364, 2008 [Epub ahead Dec 4].

Ethell, I.M. and Ethell, D.W.  Matrix metalloproteinases in brain development and remodeling: Synaptic functions and targets. J. Neurosci. Res. 85(13): 2813-2823, 2007.

Ethell, D.W., Shippy D., Cao., C., Cracchiolo, J.R., Runfeldt, M., Blake, B., Arendash, G.W.  Aβ-specific T-cells reverse cognitive decline and synaptic loss in Alzheimer's mice.  Neurobiology of Disease, Epub ahead, May 31, 2006. Click Here to View Article