Date of Award

12-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Genetics, Genomics & Informatics

Research Advisor

Junmin Peng, PhD

Committee

Young-Goo Han, PhD; Qian Li, PhD; Lindsay Scwarz, PhD; Ansley Grimes Stanfill, Ph.D, R.N., F.A.A.N.; Gang Wu, PhD

Keywords

Alzheimer;biomarker;LBD;multi-omics;Proteomics;serum

Abstract

Amyloid pathology is the central hallmark of Alzheimer’s disease (AD) and related dementias (ADRD). We analyzed the dementia with Lewy bodies disease (DLBD) proteome, a disorder also associated with amyloid pathology, and compared to the AD proteome, identifying conserved alterations in amyloid pathology and shared components in amyloid plaques, including MDK and NTN1. We additionally evaluated major AD mouse models to determine their relevance to human disease and identify shared proteomic alterations. We observed alterations in several highly conserved matrisomal components consistently im- plicated in proteomic analyses of human amyloidosis disorders. We additionally identified several pathways influenced by amyloid-pathology that were consistently shared between human AD and the 5xFAD and APPNL-G-F mouse models, including amyloid regulation, nitric oxide regulation, superoxide regulation, cell, adhesion, and cellular component organization. Finally, we investigated global proteome turnover changes in 5xFAD mice to shed light on the discrepancy between transcriptome and proteome in AD. We achieved un- precedented quantitation of protein half-lives in mice and identified decreased turnover in key amyloidome components such as APOE. Our results indicate our proteomics workflow can serve as a powerful resource for studying fundamental protein turnover, interrogating biological questions, and developing therapeutics for neurodegenerative disorders.

Declaration of Authorship

Declaration of Authorship is included in the supplemental files.

ORCID

0000-0003-1793-5630

DOI

10.21007/etd.cghs.2023.0643

Additional Files
2023-034-Yarbro-DOA.pdf (153 kB)
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