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The Skaggs Institute
for Chemical Biology
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.
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