Date of Degree

6-2020

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor

Christine Li

Committee Members

Itzhak Mano

Tadmiri Venkatesh

Cathy Savage-Dunn

Hannes Buelow

Subject Categories

Biology | Genetics

Keywords

Alzheimer's disease, APL-1, APP, UNC-52, HSPGs, C. elegans

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, impacting approximately 6 million Americans. AD is the leading cause of dementia amongst the aged population. Post mortem analysis of the brains of AD patients shows high quantities of extracellular Aβ peptide deposits, which are derived from cleavage of the amyloid precursor protein (APP). Mutations in APP and proteins responsible for APP cleavage, PSENs, greatly increase the incidence of developing AD at an early age. Despite its strong correlation to the progression of AD, the role of APP remains unclear.

Here we investigate the role of the Caenorhabditis elegans ortholog, APL-1. We identified approximately 40 proteins that interact with APL-1, and two genes that modify apl-1 activity. In particular, we showed that the heparan sulfate proteoglycan, UNC-52, is complexed with APL-1, and mutations in apl-1 enhance unc-52 phenotypes. We speculate that UNC-52 is required to sequester secreted APL-1 to help maintain APL-1-receptor interactions. Additionally, we generated two allelic mutants that showed that cdh-5 and/or tgt-1 modify apl-1 activity. These interacting proteins suggest that APL-1/APP is involved in numerous cellular functions; maintaining APL-1/APP levels impact embryonic development and lifespan. Our findings inform on the function and interactions of mammalian APP.

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