Data-driven modeling of mitochondrial dysfunction in Alzheimer's disease. (December 2018)

• Record Type: Journal Article
• Authors: Toglia, Patrick; Demuro, Angelo; Mak, Don-On Daniel; Ullah, Ghanim
• Is Part Of: Cell calcium. Volume 76(2018)
• Page Start: 23
• Page End: 35
• Publication Date: 2018-12
• Subjects: Alzheimer's disease -- Intracellular β amyloid -- Ca2+ dyshomeostasis -- Mitochondrial dysfunction; Calcium -- Metabolism -- Periodicals; Vertebrates -- Physiology -- Periodicals; Calcium -- Physiological effect -- Periodicals; Cell physiology -- Periodicals; Calcium in the body -- Periodicals; 572.516
• DOI: 10.1016/j.ceca.2018.09.003
• Languages: English
• ISSNs: 0143-4160

Abstract

Highlights: A simple four state model for IP3 R, driven by extensive single channel patch-clamp experiments. Estimating Ca 2+ and IP3 from TIRF signals due to intracellular beta amyloid. Evaluating mitochondrial dysfunction due to intracellular beta amyloid. Estimating single channel parameters from whole-cell Ca 2+ experiments. The use of Ca 2+ buffer EGTA to restore viability of cells with Alzheimer's disease pathology. Abstract: 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 Ca 2+ homeostasis as a direct consequence of the intracellular Aβ oligomers. However, little is known about the downstream effects of the resulting Ca 2+ rise on the many intracellular Ca 2+ -dependent pathways. Here we use multiscale modeling in conjunction with patch-clamp electrophysiology of single inositol 1, 4, 5-trisphosphate (IP3 ) receptor (IP3 R) and fluorescence imaging of whole-cell Ca 2+ 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 IP3 R, which is then extended to build a model for the whole-cell Ca 2+ signals. The whole-cell model is then fitted to fluorescence signals to quantify the overall Ca 2+ 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 Ca 2+ uptake and the resulting reduced mitochondrial inner membrane potential, leading to an overall lower ATP and increased production of reactive oxygen species and H2 O2 . We further show that mitochondrial function can be restored by the addition of Ca 2+ buffer EGTA, in accordance with the observed abrogation of Aβ42 cytotoxicity by EGTA in our live cells experiments.