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Title: | IDENTIFYING MOLECULAR MECHANISMS REGULATING COGNITIVE AGING USING CAENORHABDITIS ELEGANS |
Authors: | Zhou, Shiyi |
Advisors: | Murphy, Coleen |
Contributors: | Molecular Biology Department |
Keywords: | Cognitive Aging daf-2 Insulin/IGF-1 signaling |
Subjects: | Aging Neurosciences |
Issue Date: | 2024 |
Publisher: | Princeton, NJ : Princeton University |
Abstract: | As the elderly population increases worldwide, a significantly public health threat drawspeople’s attention: age-related cognitive decline. Memory loss is one of the first symptoms of aging and is exhibited in many neurodegenerative diseases, such as Alzheimer’s’ Disease (AD), Parkinson Disease (PD), frontotemporal degeneration, and other diseases related to dementia. Although concerted research efforts to identify molecules and pathways related to memory deterioration with age and to forestall dementia onset, efficient treatments for cognitive aging and its associated diseases remain elusive. Caenorhabditis elegans has been used as a model to study aging for decades. Our lab previously developed assays to measure C. elegans associative learning and short- and long-term associative memory. Using these assays, we discovered that C. elegans exhibits age-related memory decline that parallels human cognitive decreases with age. Importantly, many memory regulators, such as CREB (cAMP-response element-binding protein) and its downstream targets, are conserved across species. Moreover, the long-lived C. elegans insulin/IGF-1-like signaling (IIS) pathway mutants exhibit a significantly enhanced retention of memory capabilities compared to wild-type worms, providing a great model for investigating potential strategies to decelerate cognitive aging. Leveraging the worm’s short lifespan, various available genetic tools, and a fully mapped neuronal connectome, C. elegans presents an optimal model system for the investigation of the objectives listed above. In this thesis, I will describe my work that advances our understanding of the genetic and molecular mechanisms of cognitive aging: 1) While an analysis of young and aged neurons in wild-type C. elegans revealed a downregulation of genes associated with neuronal function and an upregulation of those involved in transcriptional regulation, longevity IIS mutants exhibit a 4 downregulation of insulin signaling genes and an upregulation of stress response genes in aging neurons. Importantly, we further identified novel memory regulators from our transcriptomic analyses that play a role in memory retention and maintenance. 2) Hypodermis nonautonomously regulates memory in C. elegans. The reduction of hypodermal IIS induces the upregulation of a Notch ligand, OSM-11. OSM-11 is secreted from the hypodermis and acts in neurons to activate neuronal Notch signaling and increase CREB-dependent memory maintenance. 3) Using an integrative systems approach that incorporates multi-evidence-based gene-mapping and network analysis-based prioritization to analyze the data from Genome-wide association studies (GWAS), we uncovered novel genetic risk factors affected by Late-onset Alzheimer’s Disease (LOAD). We discovered that genes implicated in synaptic and endolysosomal functions are dysregulated in brains affected by LOAD and tested the role of those genes in memory regulation using C. elegans. |
URI: | http://arks.princeton.edu/ark:/88435/dsp013f462876h |
Type of Material: | Academic dissertations (Ph.D.) |
Language: | en |
Appears in Collections: | Molecular Biology |
Files in This Item:
File | Description | Size | Format | |
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Zhou_princeton_0181D_14862.pdf | 23.43 MB | Adobe PDF | View/Download |
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