(178j) Investigating β-Amyloid's Early Action On Hippocampal Neurons: A Computational Study



Alzheimer’s disease (AD) is a prevalent and deadly neurodegenerative disorder characterized by the formation of senile plaques and neurofibrillary tangles. The primary protein components of the two histopathological features associated with the disease, β-amyloid peptide (Aβ) and tau, have been implicated in progression of AD. Despite extensive research into the etiology of the disease, its underlying molecular processes remain unknown. Researchers hypothesize that Aβ interacts with the cell surface preceding changes in neuronal functions and death; however, there is no consensus about the functional role of Aβ at the cell surface. We are developing a computational methodology towards identifying trends and behaviors of Aβ’s early action on hippocampal neurons. Utilizing a mathematical model of a neuron, we compare simulation results of two hypothesized mechanisms of Aβ-neuron interaction under voltage-clamp, current-clamp and high [K+] membrane depolarized conditions: Aβ’s block of the fast-inactivating potassium channel and the Aβ-induced increase in membrane conductance. Our model predicts that both mechanisms would lead to changes in ion conductances, cell excitability and calcium influx under voltage- and current-clamped conditions. Interestingly, the high [K+] membrane depolarization simulations predict an inverse trend in calcium influx between the two mechanisms.  Next, we use our methodology to study the effect of a putative Aβ ion pore on our model neuron and conduct calcium imaging experiments to probe the model’s predictions experimentally. Our results suggest that the computational modeling methodology we are developing can be used to guide experimental design towards elucidating molecular mechanisms of Aβ’s action on neurons.