Dissertations, Theses, and Capstone Projects

Date of Degree

2-2025

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor

Christine Li

Committee Members

Itzhak Mano

Cathy Savage-Dunn

Alicia Melendez

Hannes Buelow

Subject Categories

Cell Biology | Developmental Biology | Developmental Neuroscience | Genetics | Molecular and Cellular Neuroscience

Keywords

APP family, APL-1, Alzheimer’s Disease, Heparan Sulfate Proteoglycans (HSPGs), Amyloid Precursor-Like

Abstract

Alzheimer’s Disease (AD) is a devastating neurodegenerative condition that affects 6.7 million Americans annually and leads to memory loss and other cognitive impairments. There is currently no cure for the disease and current drugs only slow its onset. AD shares many overlapping symptoms with other causes of dementia, but is characterized by certain molecular hallmarks, including the presence of neurofibrillary tangles and dense plaques, composed predominantly of Aβ peptide fragments. These fragments are cleavage products of a protein called APP, a member of the APP family which also includes APLP1 and APLP2. In mammals, these proteins share overlapping expression patterns and functions, making experiments difficult to perform and interpret. The nematode Caenorhabditis elegans, however, has only one APP family member: APL-1, an ortholog of APP with the functional domains conserved. The presence of a single APP gene, along with the genetic tractability and ease of using the worm, make C. elegans an excellent model system in which to explore APP-family gene function.

In this thesis, we investigate apl-1 function from its generation to its final activation of targets. We create the first-known fluorescent translational APL-1 reporter, which we use to identify APL-1 target cells. In addition, we provide the first in vivo evidence that extracellular matrix proteins, particularly heparan sulfate proteoglycans, are involved in shuttling the extracellular domain sAPL-1 to activate its targets and also towards degradation in the coelomocytes. Finally, we identify genetic factors that control APL-1 expression, and putative effector pathways of both sAPL-1 and the APL-1 intracellular domain. Collectively, these results shed light into the entire lifecycle of APL-1, from its expression to activation of downstream effectors in its target cells, and provide insights that can be investigated further in mammalian systems to better understand APP function and identify therapeutic targets for AD.

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