Mechanistic Insights of Mitochondrial Reactive Oxygen Species in Alzheimer's Disease Models

Author

Jakob C. Green, Virginia Commonwealth UniversityFollow

DOI

https://doi.org/10.25772/52PV-CQ50

Author ORCID Identifier

https://orcid.org/0000-0002-7059-9173

Defense Date

2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmaceutical Sciences

First Advisor

Shijun Zhang

Second Advisor

Glen E Kellogg

Third Advisor

Martin Safo

Fourth Advisor

Edward J Lesnefsky

Fifth Advisor

Dong Sun

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease that results in impaired cognition, disorientation, confusion, poor judgement, and behavioral changes. The mitochondrial cascade hypothesis (MCH), which postulates that accumulating oxidative stress and mitochondrial dysfunction plays an integral role in the development of the disease, potentially upstream, in conjunction with or independent of Aβ and tau. The literature supports the critical role of mitochondrial dysfunction in the progression and development of AD, but is inconclusive about what precise role, as initiator or delegate, it performs. Regardless, the impact that oxidative stress and mitochondrial dysfunction have on AD deserves further study and investigation. Herein we confirm mitochondria and CI as the target of ZCM-I-1. In an immunocytochemistry study (ICC), photoaffinity label 1 (PAL-1) was found to colocalize with the mitochondria in MC65 cells and mouse cortical neurons, PAL-2 was able to interact and pull down NADH:FMN binding site (I_F), thermal stability assays were performed and ZCM-I-1 and JMS-103 were found to stabilize the CI subunit NDUFV1, and computational studies further supported I_F site binding. Furthermore, a PET radiotracer of JMS-103 was developed and evaluated in mice (¹⁸F-2) and found that this PET tracer exhibits high uptake in liver, a gradual increase in uptake in kidneys, and slow clearance in the blood, heart, lungs, and brain. and showed region specific binding to the brain stem, cerebellum, and midbrain suggesting higher expression levels in these regions. These results strongly encourage further development of ZCM-I-1 analogs as potential AD therapeutics and PET radiotracers.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

5-14-2021