Data-driven modeling of mitochondrial dysfunction in Alzheimer's disease

Intracellular accumulation of oligomeric forms of β amyloid (Aβ) are now believed to play a key role in the earliest phase of Alzheimer's disease (AD) as their rise correlates well with the early symptoms of the disease. Extensive evidence points to impaired neuronal Ca²⁺ homeostasis as a direct consequence of the intracellular Aβ oligomers. However, little is known about the downstream effects of the resulting Ca²⁺ rise on the many intracellular Ca²⁺-dependent pathways. Here we use multiscale modeling in conjunction with patch-clamp electrophysiology of single inositol 1,4,5-trisphosphate (IP₃) receptor (IP₃R) and fluorescence imaging of whole-cell Ca²⁺ response, induced by exogenously applied intracellular Aβ₄₂ oligomers to show that Aβ₄₂ inflicts cytotoxicity by impairing mitochondrial function. Driven by patch-clamp experiments, we first model the kinetics of IP₃R, which is then extended to build a model for the whole-cell Ca²⁺ signals. The whole-cell model is then fitted to fluorescence signals to quantify the overall Ca²⁺ release from the endoplasmic reticulum by intracellular Aβ₄₂ oligomers through G-protein-mediated stimulation of IP₃ production. The estimated IP₃ concentration as a function of intracellular Aβ₄₂ content together with the whole-cell model allows us to show that Aβ₄₂ oligomers impair mitochondrial function through pathological Ca²⁺ uptake and the resulting reduced mitochondrial inner membrane potential, leading to an overall lower ATP and increased production of reactive oxygen species and H₂O₂. We further show that mitochondrial function can be restored by the addition of Ca²⁺ buffer EGTA, in accordance with the observed abrogation of Aβ₄₂ cytotoxicity by EGTA in our live cells experiments.