Impact of β-Amyloids Induced Disruption of Ca(2+) Homeostasis in a Simple Model of Neuronal Activity

Alzheimer’s disease is characterized by a marked dysregulation of intracellular Ca(2+) homeostasis. In particular, toxic β-amyloids (Aβ) perturb the activities of numerous Ca(2+) transporters or channels. Because of the tight coupling between Ca(2+) dynamics and the membrane electrical activity, such perturbations are also expected to affect neuronal excitability. We used mathematical modeling to systematically investigate the effects of changing the activities of the various targets of Aβ peptides reported in the literature on calcium dynamics and neuronal excitability. We found that the evolution of Ca(2+) concentration just below the plasma membrane is regulated by the exchanges with the extracellular medium, and is practically independent from the Ca(2+) exchanges with the endoplasmic reticulum. Thus, disruptions of Ca(2+) homeostasis interfering with signaling do not affect the electrical properties of the neurons at the single cell level. In contrast, the model predicts that by affecting the activities of L-type Ca(2+) channels or Ca(2+)-activated K(+) channels, Aβ peptides promote neuronal hyperexcitability. On the contrary, they induce hypo-excitability when acting on the plasma membrane Ca(2+) ATPases. Finally, the presence of pores of amyloids in the plasma membrane can induce hypo- or hyperexcitability, depending on the conditions. These modeling conclusions should help with analyzing experimental observations in which Aβ peptides interfere at several levels with Ca(2+) signaling and neuronal activity.