Expression and Transcriptional Regulation of APL-1, a <i>Caenorhabditis elegans</i> APP Ortholog

<p>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 <em>Caenorhabditis elegans</em>, however, has only one APP family member: APL-1, an ortholog of APP with the functional domains conserved. The presence of a single <em>APP</em> gene, along with the genetic tractability and ease of using the worm, make <em>C. elegans </em>an excellent model system in which to explore <em>APP</em>-family gene function.</p> <p>In this thesis, we investigate <em>apl-1 </em>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 <em>in vivo </em>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.</p>

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Biology

Grantor

The Graduate School and University Center of The City University of New York

Year dc:date.available

2025

Author dc:creator

• Yang, Ji-Sup

Advisor dc:contributor.advisor

• Christine Li

Committee members dc:contributor.committeemember

• Itzhak Mano
• Cathy Savage-Dunn
• Alicia Melendez
• Hannes Buelow

• Cell Biology
• Developmental Biology
• Developmental Neuroscience
• Genetics
• Molecular and Cellular Neuroscience
• APP family
• APL-1
• Alzheimer’s Disease
• Heparan Sulfate Proteoglycans (HSPGs)
• Amyloid Precursor-Like

Repository record dc:identifier

https://academicworks.cuny.edu/gc_etds/6135

OAI identifier oai:identifier

oai:academicworks.cuny.edu:gc_etds-7250