Data-driven Modeling of Calcium Homeostasis and Bioenergetics in Alzheimer’s Disease, Down’s Syndrome and Leigh’s Syndrome.

Graduation Year

2024

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Physics

Major Professor

Ghanim Ullah, Ph.D.

Committee Member

Dmitry Voronine, Ph.D.

Committee Member

Garret Matthews, Ph.D.

Committee Member

Angelo Demuro, Ph.D.

Keywords

Ca2+ signaling, Data-driven model, Neurodegenerative disorders, ATP, Kalman Filter

Abstract

Disruption of Ca2+ homeostasis is implicated in the pathogenesis of several neurological conditions, including Alzheimer’s disease (AD), AD-like pathology in Down's Syndrome (DS) and Leigh’s Syndrome (LS). In astrocytes, disrupted intracellular Ca2+ signaling can compromise numerous brain functions, including synaptic transmission, neurovascular coupling, andbioenergetics. In our first project, we investigated the effects of brain extracts from AD patients on calcium signaling within cells and found that these extracts triggered a release of calcium within the cell, similar to synthetic components of amyloid beta plaques, a hallmark of AD. We developed a computational model to analyze how these changes in calcium signaling affect ATP production and the generation reactive oxygen species (ROS). We predicted that the abnormal calcium signals from AD brains would lead to a decrease in ATP and an increase in ROS, potentially contributing to the progressive damage observed in AD. In our second project, we investigated whether inositol 1,4,5-trisphohaste (IP3) mediated Ca2+ signaling differs between human cortical astrocytes derived from DS versus normal (NL) euploid specimens. Our experiments revealed that, although cultured, DS and NL astrocytes maintained similar resting cytosolic and luminal Ca2+ levels, DS astrocytes were severely deficient in IP3-evoked global and local Ca2+ responses. The amplitude of global Ca2+ rises in response to photo released IP3 was significantly lower in DS compared to NL astrocytes. Accordingly, DS astrocytes exhibited sparser distribution and lower density of regions associated with local Ca2+ rises, as well as a significantly lower amplitude of the local signals, consistent with a reduced number of activated IP3R channels within clusters of these channels. Detailed computational modeling revealed that the downregulation of IP3-mediated Ca2+ signaling impairs the ATP production of DS-affected astrocytes. Expanding on this, we incorporated our bioenergetic model into a model-based predictor-controller framework from modern control theory, called the Unscented Kalman Filter (UKF), to reconstruct the experimentally inaccessible variables in DS-affected astrocytes and analyze single-channel and subcellular calcium signals using the accurately generated model parameters. Finally, we developed a data-driven model for MT-AT6 mutation in LS patients – a gene which codes for the protein ATPase subunit 6 component of Complex V of the mitochondrial respiratory chain to simulate mitochondrial function and ROS production in neurons afflicted by LS. We predicted that the reduced activity of F1F0-ATPase – a key enzyme of ATP production might be a major contributor to observed ATP impairment and increased ROS production.

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