Room 209, Sanders-Brown Center On Aging
800 South Limestone Street
Lexington, KY 40536-0230
Molecular and Cellular Biochemistry
Neurodegeneration, Alzheimer’s disease
We seek to elucidate the contribution of misfolded proteins to chronic neurodegenerative diseases and to contribute to the development of therapeutic agents capable of modifying the course of these diseases. Our focus is on the Alzheimer’s ß-peptide (Aß) and its role in the cognitive decline in Alzheimer’s disease.
Aβ Peptide and RAGE Interactions in AD– The Receptor for Advanced Glycation Endproducts (RAGE) binds multiple ligands associated with oxidative stress and impacts cellular signaling. We are using affinity chromatography and LC-MS proteomics to identify proteins that associate with the RAGE ligand-binding domain (sRAGE) in AD. The molecular details of the high affinity interaction of one of these ligands, soluble oligomers of the Aβ peptide, with sRAGE are being determined.
Small molecule inhibitors of soluble Aβ oligomer assembly– Soluble non-fibrillar oligomeric forms of Aβ are highly potent neurotoxins that disrupt synaptic function. A screen for small drug-like molecules that would inhibit oligomer formation has identified several chemical structural classes that inhibit oligomer assembly as well as additional classes that dissociate preformed Aβ oligomers. We are studying the mechanisms of compound action and will be seeking funding for med chem. optimization moving towards therapeutics.
Molecular Basis of PIB Binding in the AD Brain– Our studies with a compound used as an imaging agent for clinical PET studies to measure brain Aβ pathology, Pittsburgh Compound B (PIB), indicated that AD brain has a high density of binding sites for PIB while animal models of Aβ pathology including aged non-human primates have a very low density of PIB sites, even though they have similar amounts of Aβ pathology. We propose that the formation of this site holds key information as to why AD is a uniquely human disease. We are purifying the PIB binding site from AD brain to learn how it differs in the animal models. With the support of Bayer Healthcare we will be studying the potential for an amyloid ligand fingerprint unique to AD.
Phage Display and Biofluid PIB Binding as a Biomarker for AD– Phage display of peptide sequences that bind to targets analogous to the epitope recognition sequences in antibodies is a powerful technology that has advantages over antibodies including penetrating into target crevices and not requiring immunogenicity. In collaboration with Rodney Guttmann (Sanders-Brown) we are screening for M13 bacteriophage that recognize the PIB binding site in AD brain to use to detect PIB sites released into the CSF or blood.