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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-3 (O2))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Irvine
United States
Zip Code
Sosna, Justyna; Philipp, Stephan; Albay 3rd, Ricardo et al. (2018) Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer's disease. Mol Neurodegener 13:11
Tong, Liqi; Prieto, G Aleph; Cotman, Carl W (2018) IL-1? suppresses cLTP-induced surface expression of GluA1 and actin polymerization via ceramide-mediated Src activation. J Neuroinflammation 15:127
Hainsworth, A H; Lee, S; Foot, P et al. (2018) Super-resolution imaging of subcortical white matter using stochastic optical reconstruction microscopy (STORM) and super-resolution optical fluctuation imaging (SOFI). Neuropathol Appl Neurobiol 44:417-426
Krotee, Pascal; Griner, Sarah L; Sawaya, Michael R et al. (2018) Common fibrillar spines of amyloid-? and human islet amyloid polypeptide revealed by microelectron diffraction and structure-based inhibitors. J Biol Chem 293:2888-2902
Prieto, G Aleph; Tong, Liqi; Smith, Erica D et al. (2018) TNF? and IL-1? but not IL-18 Suppresses Hippocampal Long-Term Potentiation Directly at the Synapse. Neurochem Res :
Love, Julia E; Day, Ryan J; Gause, Justin W et al. (2017) Nuclear uptake of an amino-terminal fragment of apolipoprotein E4 promotes cell death and localizes within microglia of the Alzheimer's disease brain. Int J Physiol Pathophysiol Pharmacol 9:40-57
Marsh, Samuel E; Yeung, Stephen T; Torres, Maria et al. (2017) HuCNS-SC Human NSCs Fail to Differentiate, Form Ectopic Clusters, and Provide No Cognitive Benefits in a Transgenic Model of Alzheimer's Disease. Stem Cell Reports 8:235-248
Krotee, Pascal; Rodriguez, Jose A; Sawaya, Michael R et al. (2017) Atomic structures of fibrillar segments of hIAPP suggest tightly mated ?-sheets are important for cytotoxicity. Elife 6:
Hernandez, Michael X; Jiang, Shan; Cole, Tracy A et al. (2017) Prevention of C5aR1 signaling delays microglial inflammatory polarization, favors clearance pathways and suppresses cognitive loss. Mol Neurodegener 12:66
Thielens, Nicole M; Tedesco, Francesco; Bohlson, Suzanne S et al. (2017) C1q: A fresh look upon an old molecule. Mol Immunol 89:73-83

Showing the most recent 10 out of 281 publications