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The Skaggs Institute
for Chemical Biology


Scientific Report 2008




Cytokine Inflammatory Signaling in Obesity and Neurodegeneration

T. Bartfai, B. Conti, I. Tabarean, M. Sanchez-Alavez, O. Osborn, I. Klein

The "endogenous pyrogen," the proinflammatory cytokine IL-1, which has been a major topic of our studies, is a key cytotoxic agent for the pancreatic beta cells that produce insulin. In obesity, increased insulin resistance necessitates the production and release of more and more insulin to control blood glucose levels. We wish to know if blocking IL-1 signaling in obese individuals can protect the beta cells and thus postpone or block the development of type 2 diabetes and the need for insulin injection as the endogenous production of insulin decreases and finally stops. We plan to use AS-1 and EM163, blockers of signaling by Toll-like receptors that were developed in collaboration with J. Rebek, the Skaggs Institute. These low molecular weight blockers, which are mimetics of the adaptor protein myeloid differentiation factor 88, are ideal for oral administration and may be used for chronic treatment of obesity/type 2 diabetes.

As proof of principle of the therapeutic value of blocking IL-1 signaling, we used high-affinity mouse monoclonal antibodies that neutralize IL-1. In obese animals with stressed, enlarged, and/or dying beta pancreatic cells, blockade of cytotoxic IL-1 signaling protected beta cells and prevented enlargement of the cells. These findings suggest that such blockade would likely postpone the development of type 2 diabetes, for which obesity, alongside age, is a major risk factor. This study opens the way for the use of molecules such AS-1 and EM 163 and their derivatives in treatment of obesity to postpone development of type 2 diabetes.

IL-1 is also a major inflammatory and neurogenesis-promoting signal in the developing brain. Blockade of L-1 signaling during development blunts the division of nerve cells and thus produces cognitive deficits. This effect is an important caveat for using blockers of IL-1 signaling in nonadults.

The protein transthyretin can produce plaques similar to the proteolytic degradation product of the amyloid precusor protein, which forms amyloid plaques, the hallmark of Alzheimer's disease. It was assumed that transthyretin acts as "seed" in the formation of amyloid plaques and that it indirectly may influence the concentration and actions of the neurotoxic monomers amyloid β-peptide1-40/42. However, collaborative studies with J.N. Buxbaum, Scripps Research, in transgenic mice that overproduce the amyloid peptide indicated the opposite. Transthyretin can protect the brain from the neurotoxic effects of amyloid β-peptides, probably by promoting the clearance of the neurotoxic monomers, and thus may be part of endogenous neuroprotection mechanisms. These findings open a previously unknown therapeutic possibility for treatment of Alzheimer's disease.

Publications

Buxbaum, J.N., Ye, Z., Reixach, N., Friske, L., Levy, C., Das, P., Golde, T., Masliah, E., Roberts, A.R., Bartfai, T. Transthyretin protects Alzheimer's mice from the behavioral and biochemical effects of A β toxicity. Proc. Natl. Acad. Sci. U. S. A. 105:2681, 2008.

Osborn, O., Brownell, S.E., Sanchez-Alavez, M., Salomon, D., Gram, H., Bartfai, T. Treatment with an interleukin 1 beta antibody improves glycemic control in diet-induced obesity. Cytokine 44:141, 2008.

Spulber, S., Oprica, M., Bartfai, T., Winblad, B., Schultzberg, M. Blunted neurogenesis and gliosis due to transgenic overexpression of human soluble IL-1ra in the mouse. Eur. J. Neurosci. 27:549, 2008.

 

Tamas Bartfai, Ph.D. Professor
Chairman, Department of Molecular and Integrative Neurosciences
Director, Harold L. Dorris Neurological Research Institute

Harold L. Dorris Neurological Research Institute