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Sirui Jiang_Thesisv3.pdf (2.41 MB)

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Mitochondrial Dynamic Abnormalities in Alzheimer's Diease

Jiang, Sirui
http://rave.ohiolink.edu/etdc/view?acc_num=case1536608714970424

Abstract Details

2018, Doctor of Philosophy, Case Western Reserve University, Pathology.
Alzheimer’s Disease (AD) is the most common cause of dementia leading to progressive memory loss and neurodegeneration in the hippocampus and frontal cortex. While it has been shown that mitochondrial dysfunction is an early and prominent feature in the progression of AD, it is unclear whether mitochondrial dysfunction itself can lead to neurodegeneration in AD-affected brain regions. Evidence has already suggested that various mitochondrial dynamic proteins (DLP1, OPA1, Mfn1, Mfn2, Fis1) are altered in AD and that there is an imbalance of mitochondrial fission and fusion yet there is a knowledge gap of whether this altered dynamics leads to neurodegeneration and what mechanisms lead to altered mitochondrial proteins in AD. To answer these questions, we created an Mfn2 conditional knockout mouse to recapitulate mitochondrial fragmentation phenotype in the hippocampus and frontal cortex. We found that indeed loss of mitochondrial fusion leads to mitochondrial morphological and bioenergetics abnormalities. These early changes lead to a series of events including oxidative stress, inflammation, and microtubule abnormalities that precede neurodegeneration. To understand the underlying mechanisms leading to loss of important mitochondrial dynamic proteins in AD, we treated primary neurons with amyloid-beta derived diffusible ligands to mimic AD and we found that the loss of DLP1 and Mfn2 is attributed to the calcium-activated protease, calpain. We also found that calpain specifically cleaves DLP1 leading the appearance of several cleavage fragments in both AD transgenic mice as well as AD patient brains. Altogether, these studies show that loss of mitochondrial dynamics could lead to neurodegeneration and that the loss of mitochondrial dynamic proteins in AD could be through the activity of calcium-activated proteases such as calpain.
Xiongwei Zhu, PhD (Advisor)
Xinglong Wang, PhD (Advisor)
Shu Chen, PhD (Committee Chair)
Hoppel Charles, MD (Committee Member)
Dubyak George, PhD (Committee Member)
123 p.
Neurosciences; Pathology
Alzheimers Disease; Mitochondria; Mitochondrial Dynamics

Recommended Citations

Citations

  • Jiang, S. (2018). Mitochondrial Dynamic Abnormalities in Alzheimer's Diease [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1536608714970424

    APA Style (7th edition)

  • Jiang, Sirui. Mitochondrial Dynamic Abnormalities in Alzheimer's Diease. 2018. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1536608714970424.

    MLA Style (8th edition)

  • Jiang, Sirui. "Mitochondrial Dynamic Abnormalities in Alzheimer's Diease." Doctoral dissertation, Case Western Reserve University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1536608714970424

    Chicago Manual of Style (17th edition)

case1536608714970424
207
© 2018, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.