Abstract

Alzheimer's Disease (AD) is a neurological disorder associated with brain mass loss and cognitive decline. It affects millions of elderly people and is currently uncurable. Since 1906, when the disease was first described, researchers have uncovered many components of AD pathology. However, it is now evident that curing Alzheimer's Disease will require intervention before the pathological onset of amyloid beta plaque deposition, tau neurofibrillary tangles, and associated neuronal loss. Studying AD from the perspective of early intervention requires special attention to small changes that may disrupt the normal processing of cells. Cells undergo a natural cycle of creation and destruction of biomolecules such as proteins, lipids, and carbohydrates, to maintain balance based on the cell's needs (homeostasis). This dynamic equilibrium is important for adapting to small changes to eventually bring the system back to the desired homeostatic state. Proteins are enzymatic components that work to mediate changes in homeostasis. Thus, the premise of this work is to understand changes in homeostasis through the lens of the proteome (proteostasis). Though many homeostatic states can exist, some are superior to others. In the case of disease, we suspect a small adaptation in homeostasis leads to an environment in which disease pathology slowly progresses. For example, the accumulation of amyloid beta plaques in Alzheimer's Disease is not a sudden event, rather, a normal enzymatic cleavage of amyloid precursor protein (APP) that preferentially produces a longer and aggregate prone peptide (Aβ42). Though cleavage of APP occurs in healthy individuals, and can produce Aβ42, the balance of alternative cleavage products does not result in AD. Thus, some underlying homeostatic adaptation may be causing preferential production of Aβ42 in AD patients. Many hypotheses including plaque deposition, endosomal processing malfunction, mitochondrial dysfunction, ineffective clearance mechanisms, and genetic predisposition have been proposed regarding early onset of AD. The scope of the included work is to assess brain homeostasis using global proteomic approaches to unite the proposed mechanisms of AD onset. This work describes currently proposed AD risk factors while diving into the largest genetic risk factor (ApoE4), discusses benefits and deficiencies of modeling AD, and introduces protein homeostasis through abundance and kinetic measurements.

Degree

PhD

College and Department

Computational, Mathematical, and Physical Sciences; Chemistry and Biochemistry

Rights

https://lib.byu.edu/about/copyright/

Date Submitted

2026-08-12

Document Type

Dissertation

Keywords

Proteomics, Brain Proteostasis, Protein kinetics, ApoE isoforms, Alzheimer's Disease, Aging, Alzheimer's Disease Risk Factors, Mouse Modeling

Language

english

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