An Investigation of Possible Cell Signaling Pathways Induced by Aggregated Beta-Amyloid Peptide

Wednesday, November 10, 2010
Hall 1 (Salt Palace Convention Center)
Arundhathi Venkatasubramaniam and Theresa A. Good, Chemical and Biochemical Engineering, University of Maryland Baltimore County, Baltimore, MD

Alzheimer's disease (AD) is a progressive dementing disorder that primarily affects the elderly population. Approximately 5-10% of the population older than 65 years and as many as 50% of those older than 85 years are estimated to have the disease. The condition is characterized by a number of neuropathological features such as the presence of amyloid plaques and neurofibrillary tangles. The primary protein component of amyloid plaques is the beta amyloid (Aβ peptide). The amyloid hypothesis suggests that the accumulation of Aβ in the brain is the primary influence driving AD pathogenesis. Many investigators have shown that aggregated forms of Aβ are toxic to neurons, and tried to identify mechanisms of neurodegeneration. However, the earliest signs of AD are loss of memory, not rapid neuron death, thus, in our study we have sought to investigate those Aβ-cell interactions that might be linked to the chemical reactions within neurons associated with learning and memory. In particular the effect of the aggregated form of beta-amyloid on neurons with respect to phosphorylation of proteins in the cytoplasm is studied. A combination of flow cytometry and imaging techniques are used to probe the pathway of cell signaling events that occur in SY5Y neurons on exposure to beta-amyloid peptide in it's aggregated state over a range of concentration and time of exposure. The results indicate that Beta-amyloid(1-42) initiates the phosphorylation of tyrosine on proteins in the cell that can be blocked by specific tyrosine kinase inhibitors. Some evidence in the lab suggests that Aβ activates a member of the Src tyrosine kinase family. The kinase activation appears to be a function of Aβ structure and may be modulated by modification of specific amino acid residues on the Aβ surface. The Aβ induced kinase activation could initiate a signaling cascade that leads to changes in receptor and ion channel function that would adversely affect learning and memory in vivo. Thus, as we search for a mechanism by which Aβ alters pathways associated with learning and memory, we believe that any change in activity away from a set point or control levels might lead to loss of function.

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