Author ORCID Identifier

https://orcid.org/0000-0003-4922-1712

Date of Graduation

12-2021

Document Type

Thesis (MS)

Program Affiliation

Biomedical Sciences

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Rodrigo Morales, PhD

Committee Member

Andrey Tsvetkov, PhD

Committee Member

Sheng Zhang, PhD

Committee Member

Assaf Gottlieb, PhD

Committee Member

Akihiko Urayama, PhD

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder that will progressively impair cognitive function. AD is the leading source of dementia, and affects one third of the senior citizens in the United States. Aging is the primary risk factor for AD and due to the expected rise in human lifespan worldwide, the occurrence rate of AD diagnosis is projected to increase. This observation is increasingly alarming when considering there is no treatment for reversal or prevention of AD yet.

AD is characterized by gross pathological hallmarks in the brain. These include the extracellular accumulation of misfolded amyloid-beta (Aβ) and the intraneuronal buildup of tau neurofibrillary tangles (NFTs). Compelling evidence suggests that Aβ triggers tau accumulation. Both of these disease-associated proteins are known to contribute to the typical AD associated clinical signs. Interestingly, these proteins have been shown to display several features similar to those seen in infectious prions, such as their conformational strain diversity. Prion strains trigger diseases that may substantially vary in their pathological and clinical aspects. One example of strain diversity in Aβ can be found in the synthetic 2F and 3F fibrils. These aggregates were originally generated by Petkova et al. by modifying protein aggregation protocols. These strains were thoroughly characterized by their structural features, convincingly showing that misfolded Aβ can adopt different conformations. This paper explores Aβ seed strains differentially influencing the conformation of tau aggregates in order to promote altered tau pathology.

Keywords

Alzheimer's, Prion, Protein Misfolding, Cross-Seeding

Available for download on Thursday, December 15, 2022

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