Alzheimer's disease (AD) is the most common form of dementia afflicting over 5 million people in the United States, and this number is expected to double by the year 2050.Neither the exact cause nor a cure for AD have yet to be found despite years of interdisciplinary research. One common feature of AD is the production of oxidative stress due in part to buildup of amyloid (A�) plaques in the brain of patients.  This is known to lead to death of neurons and loss of cognitive function. Mounting evidence links metal ion dyshomeostastis and miscompartmentalization with subsequent deposition of A� and concomitant free radical generation as one source of this stress which causes neuronal death although others exist as well. When redox active metal ions bind to amyloid, Fenton chemistry cascades to produce a plethora of reactive oxygen species (ROS) known to cause lipid, DNA, and protein oxidation, impaired synaptic and axonal communication, neuronal death, and mitochondrial dysfunction. This body of work has established the role of metal ions as a component of the amyloid cascade hypothesis to form the �metal hypothesis of Alzheimer's disease,� which notes that the interactions of A� and metal ions, along with atypical metal ion homeostasis, are coupled with the neuropathogenesis of AD. Our group has developed new molecules composed of N-heterocyclic amines that are designed to bind the metal-ions associated with AD as well as engender antioxidant capacity. Our work will show that these novel ligand systems have low toxicity in multiple cell lines and provide protection against both amyloid and metal-induced assaults in neuronal cell culture.  Moreover we will focus on the interaction of the molecules with amyloid peptide provided by fluoroscence and 15N-SOFAST NMR Spectroscopy.

Hybrid small molecules using lipoic acid as antioxidant chelators designed to target amyloid and the molecular features associated with neurodegenerative disorders

247th National Meeting (2014)

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