Data-Driven Modeling of Mitochondrial Dysfunction in Alzheimer's Disease

Authors

Patrick Toglia, University of South FloridaFollow
Angelo Demuro, University of California
Don-On D. Mak, University of Pennsylvania
Ghanim Ullah, University of South FloridaFollow

Document Type

Article

Publication Date

12-2018

Keywords

Alzheimer's disease, Intracellular β amyloid, Ca2+ dyshomeostasis, Mitochondrial dysfunction

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.ceca.2018.09.003

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.

Was this content written or created while at USF?

Yes

Citation / Publisher Attribution

Cell Calcium, v. 76, p. 23-35

Scholar Commons Citation

Toglia, Patrick; Demuro, Angelo; Mak, Don-On D.; and Ullah, Ghanim, "Data-Driven Modeling of Mitochondrial Dysfunction in Alzheimer's Disease" (2018). Physics Faculty Publications. 49.
https://digitalcommons.usf.edu/phy_facpub/49