Project 2: AB and IL-1B Suppress BDNF Signaling and the Regulation of Synaptic PlasticityInflammation is a common mechanism associated with aging and neurodegenerative diseases such as Alzheimer'sdisease (AD), Parkinson's disease (PD), AIDS dementia, and autoimmune disease. Proinflammatory cytokinessuch as IL-1 (3 become elevated in the brain and are associated with an increased risk of cognitive decline andneurodegeneration. Further, in AD and AD/PD, (3-amyloid (A|3) accumulates and is linked to variouspathological cascades that can converge on neuronal degeneration. While it is usually assumed that themechanism by which these factors cause brain dysfunction is neuronal degeneration, this may not be the only orthe earliest mechanism. We propose that a chronic elevation in A|3 and IL-1|3 interferes with neuronal functionby inducing a state of 'neurotrophic factor resistance' similar in many ways to insulin/IGF-1 resistance.Specifically, A(3 and IL-1 (3 interfere with signal transduction induced by the neurotrophic factor BDNF, resultingin impaired signaling, increased vulnerability of neurons and interference with activity dependent plasticity such aslong term potentiation. We propose 3 Aims. First, we will determine if the impairment of IL-1 on TrkBregulation resides at the level of the docking protein IRS-1, determine if IL-1 impairs the BDNF dependentinduction of synaptic vesicles proteins reduced in AD, and examine the effect of IL-1 on BDNF-dependent thetaLTP. Second, we will then determine if IL-1 can act in concert with A_ and exert an additive or synergisticreduction on TrkB signal transduction. Third, we will examine TrkB retrograde signaling. BDNF/TrkB signalingat synapses depends on local signal transduction and also retrograde TrkB retrograde transport to the soma. Wewill use a novel microfluidic culture chamber, which allows the selective isolation of axons and the fluidicisolation of axonal microenvironment. Using this chamber, our preliminary data suggest retrograde TrkBsignaling is compromised in APP Tg2576 neurons. We will follow up this exciting lead, define the process anddetermine the mechanisms. Overall, the proposed experiments will evaluate new possible mechanisms ofneurotrophic factor resistance that may compromise brain function and plasticity and increase the risk forconversion to more advanced disease states.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG000538-29A1
Application #
7347987
Study Section
Special Emphasis Panel (ZAG1-ZIJ-3 (O2))
Project Start
1997-08-01
Project End
2013-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
29
Fiscal Year
2008
Total Cost
$250,102
Indirect Cost
Name
University of California Irvine
Department
Type
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
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