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

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 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.

• Authors: Patrick Toglia, Angelo Demuro, Don-On Daniel Mak, Ghanim Ullah
• Journal: Cell calcium (Cell Calcium) Vol. 76 Pg. 23-35 (12 2018) ISSN: 1532-1991 [Electronic] Netherlands
• PMID: 30248575 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Inositol 1,4,5-Trisphosphate Receptors
• Calcium

Topics

• Alzheimer Disease (metabolism, pathology)
• Amyloid beta-Peptides (metabolism)
• Animals
• Calcium (metabolism)
• Data Analysis
• Inositol 1,4,5-Trisphosphate Receptors (metabolism)
• Mitochondria (metabolism, pathology)
• Models, Biological
• Optical Imaging
• Patch-Clamp Techniques
• Xenopus laevis