Meyerhoff Graduate Fellows Program

Student Profiles

Natasha P. Wilson
Chemical, Biochemical and Environmental Engineering

Area of Doctoral Study: Chemical and Biochemical Engineering

Undergraduate Institute: University of Maryland, Baltimore County

Research Advisors: Theresa Good, Ph.D and Mariajosé Castellanos, Ph.D

Description of Research

Alzheimer’s disease is a prevalent and deadly disease characterized by the formation of senile plaques (β-amyloid, Aβ) and neurofibrillary tangles (tau hyperphosphorylation) that have been implicated in neuronal death.  Despite extensive research into the etiology of the disease, its underlying molecular processes remain unknown. The prevailing hypothesis for how neuronal dysfunction and death occurs in Alzheimer’s disease is known as “the amyloid hypothesis”, which posits that the formation of Aβ from the cleavage of the Amyloid Precursor Protein (APP) subunit leads to a cascade of events within the cell, including disturbances in calcium homeostasis, and ultimately to the cell’s demise.  It has been established that Aβ interacts with the neuronal membrane preceding changes in the membrane properties and neuronal death; however, there is no consensus about the functional role of Aβ in the membrane.  We hypothesize that disruption of Ca2+ homeostasis, resulting in increases in intracellular calcium levels, occurs because of Aβ’s interaction with the membrane, and plays a pivotal role in neuronal death.  Therefore, any mechanism that explains Aβ’s interactions with the membrane and its function will result in an increase in intracellular calcium levels in the neuron.  To test this hypothesis, we have developed a mathematical model neuron to screen mechanisms of proposed Aβ-membrane interactions by Aβ’s affect on calcium transport into the neuron.  Some examples of these mechanisms are:  formation of a cation-selective channel, dysregulation of a native ion channel or receptor, or an increase in general membrane permeability.  We are combining our modeling effort with quantitative live-cell calcium imaging of neuron and neuron-like cells, under exposure to Aβ, to determine pass/fail criteria for screening models of Aβ-membrane interactions, and to test predictions from the model.  The final screened model will be used to further examine the effects of Aβ on Ca2+-dependent cell signaling pathways that may lead to changes in synaptic plasticity, neuronal dysfunction and cell death.   The goal of this research is to gain a deeper understanding of the molecular level events that occur in the neuron as a consequence of Aβ-membrane interactions. The results will provide a link between observed phenomena, such as changes in neuronal membrane properties and neurotoxicity in the presence of Aβ, and learning dysfunction and memory loss associated with the disease.  This understanding can provide new inroads for drug design of treatments for Alzheimer’s disease.

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