The objective of this proposal is to study, in human and experimental paradigms, the sequence of events engendered by the presence of over representation of chromosome 21 gene products that give rise to the Alzheimer-type neurodegenerative changes and cognitive decline that are characteristic of middle age in Down's patients. We propose that trisomy 21 gene loading directly promotes synthesis of beta-amyloid precursor protein (betaAPP) and release of its secreted fragments (sAPP) that, in turn, activates microglia and induces synthesis and release of interleukin-1 (IL-1) the principle proinflammatory cytokine. We further propose that it is through the actions of this cytokine that neurodegenerative events are perpetuated via a self propagating cascade that we termed the cytokine cycle. For example, IL-1 (i) upregulates the expression and processing of beta-amyloid precursor protein (betaAPP) and the activity and mRNA levels of acetyl cholinesterase (AchE) in neurons; and (ii) induces synthesis and release of S100beta in astrocytes. These IL-1 mediated events increase the potential for neuronal dysfunction by AchE-induced degradation of the Alzheimer's and Down's related neurotransmitter acetyl choline, as well as by S100beta-induced cell death through increases in neuronal calcium, excessive synthesis of betaAPP, and inappropriate growth of neurites. We postulate, in view of IL-1 based actions and the potential of chronic IL-1 overexpression in Down's to directly and indirectly promote neuronal injury and death, that the progression of Alzheimer-type changes are driven by self propagating events in the cytokine cycle. We will determine temporal and spatial relationships between cytokine cycle elements and neuronal cell injury and death in Down's syndrome and in partial trisomy 16 animal models. An implantation paradigm for delivering cytokine cycle elements and appropriate blockers together with cell co-culture system models will be used to define mechanisms responsible for these relationships. Accomplishment of our aims will elucidate the pathogenic mechanisms underlying the cognitive decline apparent at middle age in Down's patients and provide targets for possible therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD037989-04
Application #
6660383
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Vitkovic, Ljubisa
Project Start
2000-07-01
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
4
Fiscal Year
2003
Total Cost
$246,996
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Other Health Professions
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
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