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2006 Grant - Klein
Synaptic Targeting by ADDLs as a Basis for Specific Neurodegeneration in Alzheimer's Disease
William L. Klein, Ph.D.
2006 Investigator-Initiated Research Grant
The "amyloid hypothesis" posits that Alzheimer's disease is triggered by a small protein fragment called beta-amyloid. While this hypothesis has been supported by a vast amount of scientific data, there are several important questions that it fails to answer. Scientists have been puzzled for years, for example, by the fact that pathology is restricted to just few types of neurons even though beta-amyloid is produced throughout the brain, and indeed, in many different cells in the body.
William Klein, Ph.D, and colleagues plan to address that conundrum. They propose that Alzheimer's disease pathology is limited to specific cells because the most toxic assemblages of beta-amyloid, the so called amyloid-beta-derived diffusible ligands (ADDLs), bind with hormone-like specificity to proteins that are only found on the surface of specific subtypes of neurons.
Initial work from Klein's laboratory suggests that ADDLs bind to synapses -specialized junctions that facilitate communication between neurons. Not all of these synapses are the same. Some carry specific types of neurotrans-mitter receptors, the docking sites for the chemical messengers that pass between neurons. Initial work from Klein's team indicated that ADDLs bind to the NMDA receptor.
They now plan to test if ADDL pathology depends on this interaction and will try to identify proteins that mediate the binding. This could ultimately lead to the development of ADDL antagonists, small molecules that prevent ADDLs from binding to the NMDA receptors and that may be of therapeutic benefit.