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Studies on Brain Aging and Alzheimer's Disease Using Mass Spectrometry, Organic Synthesis, and Biostatistics.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Studies on Brain Aging and Alzheimer's Disease Using Mass Spectrometry, Organic Synthesis, and Biostatistics./
Author:	Shuken, Steven R.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
Description:	234 p.
Notes:	Source: Dissertations Abstracts International, Volume: 83-05, Section: B.
Contained By:	Dissertations Abstracts International83-05B.
Subject:	Teaching. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28812950
ISBN:	9798494455482

Studies on Brain Aging and Alzheimer's Disease Using Mass Spectrometry, Organic Synthesis, and Biostatistics.
Shuken, Steven R.

Studies on Brain Aging and Alzheimer's Disease Using Mass Spectrometry, Organic Synthesis, and Biostatistics. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 234 p.

Source: Dissertations Abstracts International, Volume: 83-05, Section: B.

Thesis (Ph.D.)--Stanford University, 2021.

This item must not be sold to any third party vendors.

Brain aging is a poorly understood process widely understood to be a major causative factor in age-associated neurodegenerative diseases such as Alzheimer's disease (AD). Proteins are involved in brain aging and neurodegeneration in many ways, and their functions and dysfunctions are dependent upon their abundances and their three-dimensional chemical structures. Emergent tools in multiple chemistry subfields, including mass spectrometry-based proteomics, enable a more detailed understanding of the states of proteins in these systems. In this Dissertation, I describe the usage of two chemistry techniques, primarily mass spectrometry-based proteomics and secondarily synthetic organic chemistry, to study proteins involved in brain aging and AD. In addition, I describe the utilization of existing statistical methods and the development of new statistical tools to further enhance our understanding of changing proteomes.The first Chapter in this Dissertation contextualizes my work in the Wyss-Coray Laboratory by providing the background for my transition from the Department of Chemistry at Stanford University, where I earned a Master of Science degree, to the Department of Neurology and Neurological Sciences in the Stanford University School of Medicine. This Chapter lays the groundwork for the lens, rooted in chemistry, through which I have viewed the fields of brain aging and AD as I have pursued subsequent studies in the Wyss-Coray Laboratory.Chapters 2 and 3 serve as technical introductions. Chapter 2 presents historical and biological background on the fields of brain aging and AD with an emphasis on the role of proteins. In Chapter 3, mass spectrometry-based proteomics is introduced, first with an in-depth conceptual and practical review of basic aspects, and then with an introduction to two advanced topics relevant to my work in later chapters: data-independent acquisition (DIA) and limited proteolysis-mass spectrometry (LiP-MS).The primary results presented in this Dissertation are the subjects of Chapters 4--7. In Chapter 4, the centerpiece of the Dissertation, the main focus of my graduate work is presented. This Chapter describes the usage of LiP-MS to study brain aging by assessing changes in both protein abundance and protein chemical structure that occur in the cerebrospinal fluid (CSF) with agingIt describes modifications of preexisting LiP-MS analysis methods that I employed to address challenges posed by the study. The resulting analytical workflow was developed and packaged into a tool that will allow others to easily perform sophisticated LiP-MS analyses to study mammalian biology. This work culminated in the discovery of a covalent immunocomplex in CSF previously unknown to exist in CSF, the Cd5l-IgM complex, whose abundance increases significantly in the CSF during aging. Chapter 5 discusses one persistent weakness of LiP-MS: LiP-MS results are ambiguous with respect to specific chemical/structural change. Also, it is still not entirely known which chemical changes in proteins are detectable by LiP-MS and which are not. In particular, changes in N-glycosylation, a post-translational modification found on the vast majority of CSF proteins, has not been shown to be detectable by LiP-MS. By enzymatically removing N-glycans from CSF proteins using PNGase F and performing LiP-MS, LiP-MS was shown to detect structural changes caused by changes in N-glycosylation for the first time.

ISBN: 9798494455482Subjects--Topical Terms:

517098
Teaching.

Studies on Brain Aging and Alzheimer's Disease Using Mass Spectrometry, Organic Synthesis, and Biostatistics.
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520 $a Brain aging is a poorly understood process widely understood to be a major causative factor in age-associated neurodegenerative diseases such as Alzheimer's disease (AD). Proteins are involved in brain aging and neurodegeneration in many ways, and their functions and dysfunctions are dependent upon their abundances and their three-dimensional chemical structures. Emergent tools in multiple chemistry subfields, including mass spectrometry-based proteomics, enable a more detailed understanding of the states of proteins in these systems. In this Dissertation, I describe the usage of two chemistry techniques, primarily mass spectrometry-based proteomics and secondarily synthetic organic chemistry, to study proteins involved in brain aging and AD. In addition, I describe the utilization of existing statistical methods and the development of new statistical tools to further enhance our understanding of changing proteomes.The first Chapter in this Dissertation contextualizes my work in the Wyss-Coray Laboratory by providing the background for my transition from the Department of Chemistry at Stanford University, where I earned a Master of Science degree, to the Department of Neurology and Neurological Sciences in the Stanford University School of Medicine. This Chapter lays the groundwork for the lens, rooted in chemistry, through which I have viewed the fields of brain aging and AD as I have pursued subsequent studies in the Wyss-Coray Laboratory.Chapters 2 and 3 serve as technical introductions. Chapter 2 presents historical and biological background on the fields of brain aging and AD with an emphasis on the role of proteins. In Chapter 3, mass spectrometry-based proteomics is introduced, first with an in-depth conceptual and practical review of basic aspects, and then with an introduction to two advanced topics relevant to my work in later chapters: data-independent acquisition (DIA) and limited proteolysis-mass spectrometry (LiP-MS).The primary results presented in this Dissertation are the subjects of Chapters 4--7. In Chapter 4, the centerpiece of the Dissertation, the main focus of my graduate work is presented. This Chapter describes the usage of LiP-MS to study brain aging by assessing changes in both protein abundance and protein chemical structure that occur in the cerebrospinal fluid (CSF) with agingIt describes modifications of preexisting LiP-MS analysis methods that I employed to address challenges posed by the study. The resulting analytical workflow was developed and packaged into a tool that will allow others to easily perform sophisticated LiP-MS analyses to study mammalian biology. This work culminated in the discovery of a covalent immunocomplex in CSF previously unknown to exist in CSF, the Cd5l-IgM complex, whose abundance increases significantly in the CSF during aging. Chapter 5 discusses one persistent weakness of LiP-MS: LiP-MS results are ambiguous with respect to specific chemical/structural change. Also, it is still not entirely known which chemical changes in proteins are detectable by LiP-MS and which are not. In particular, changes in N-glycosylation, a post-translational modification found on the vast majority of CSF proteins, has not been shown to be detectable by LiP-MS. By enzymatically removing N-glycans from CSF proteins using PNGase F and performing LiP-MS, LiP-MS was shown to detect structural changes caused by changes in N-glycosylation for the first time.
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