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In pursuit of small molecule based prevention of Alzheimer's disease : defining the mechanistic pathway via bilayer electrophysiology


The prevailing hypothesis for pathology of Alzheimer's disease (AD) proposes that amyloid-beta (A[Beta]) peptides are the toxic element. Small oligomers of A[Beta] are believed to induce uncontrolled, neurotoxic ion flux across cellular membranes. The resulting inability of neurons to regulate their intracellular concentration of ions, particularly calcium ions, has been associated with cell death and may contribute to the cognitive impairment typically seen in AD patients. The mechanism of the ion flux is not fully understood, but the most direct mechanism of membrane disruption would be the formation of channel-like pores. Structural models and experimental evidence suggest that A[Beta] pores form from an assembly of loosely-associated mobile [Beta]-sheet subunits. However, further understanding of the underlying mechanism of AD will be crucial to our ability to design highly efficacious therapeutics. The dissertation focuses on the application of bilayer electrophysiological recordings to the study and determination of the mechanistic pathway of A[Beta] pathophysiology in AD. Biophysical characterization of the highly cytotoxic pyroglutamate- modified A[Beta] (A[Beta]pE) is first presented. We show that A[Beta]pE activity is shifted to higher conductance events, which could explain their increased toxicity. Next, we introduce, and provide proof of concept for, a newly developed analysis tool which more accurately depicts cytotoxicity than traditional channel analysis methods. Finally, we use two small molecule drug candidates to test efficacy and gain insight into the mechanism of pore formation. From the results we suggest structural targets for future therapeutic design. This work advances the understanding of the underlying mechanism of AD pathophysiology by pore formation and will aid the design of small molecule pharmaceuticals for the treatment/ prevention of this devastating disease

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