Dissertations, Theses, and Capstone Projects

Date of Degree

9-2025

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy

Program

Biochemistry

Advisor

Maria Figueiredo-Pereira

Committee Members

Peter Serrano

Carmen Melendez-Vasquez

Makoto Ishii

Javier Pacheco-Quinto

Subject Categories

Biochemistry | Biology | Cell Biology | Molecular and Cellular Neuroscience

Keywords

Alzheimer's Disease, Cellular Biology, Drug repurposing, Neuroscience, Neurodegeneration, Drug Development

Abstract

Alzheimer’s Disease (AD) is a complex neurodegenerative disease that has limited treatment options and no cure. AD is characterized by robust pathology including extracellular amyloid beta plaques, intracellular neurofibrillary tangles, neuronal and synaptic loss, neuroinflammation, and brain atrophy. AD presents with cognitive decline and memory loss but only years after neuropathology has started to accumulate. This robust pathology has made AD difficult to treat and highlights the need for therapeutics that modulate multiple pathways. Agomelatine (AGO) was selected by a high-throughput machine learning drug repurposing algorithm by our collaborator Dr. Lie Xie (Hunter College Dept. of Comp. Sci.) as having repurposing potential for AD. AGO is a synthetic derivative of melatonin and is currently used as an antidepressant in Europe, Asia, and Australia (brand name Valdoxan). AGO elicits a synergistic mechanism of action acting as both an agonist at the MT1/MT2 melatonin receptors and an antagonist at the 5HT2c serotonin receptor.

The overall goal of my studies was to investigate whether the antidepressant drug AGO has therapeutic potential to treat AD. My central hypothesis is that AGO has therapeutic potential for treating AD through its neuroprotective synergistic mechanism as an agonist at the MT1/MT2 melatonin receptors and an antagonist at the 5HT2C serotonin receptor.

The results of my studies are addressed in the following chapters:

1. Chronic AGO treatment mitigates cognitive decline and pathology in a sex-specific manner in a transgenic rat model of AD.

I showed that chronic treatment with AGO preserved hippocampal-dependent spatial memory and learning in female TgF344-AD (Tg-AD) rats. This mitigation of cognitive deficits was accompanied by restoring hippocampal microglial activation to a homeostatic state and decreasing hyperphosphorylation of tau in female. Interestingly, AGO decreased Aβ deposition in the hippocampal dentate gyrus of male Tg-AD rats but did not restore their spatial learning, microglial, or tau phosphorylation levels.

2. AGO exhibits a neuroprotective mechanism of action in a transgenic rat model of AD.

Transcriptomic analysis showed that AGO increased expression of synaptic pathways in female Tg-AD treated rats compared to Tg-AD nontreated (NT), giving insight into AGO’s mechanism of action. Additionally in both male and female Tg-AD rats, AGO decreased markers of oxidative stress at the transcriptomic level.

3. AGO promotes viability and neuroprotection in a human induced pluripotent stem cell (iPSC)-derived cortical neuron model of AD.

AGO’s mechanism of action was further explored using a human iPSC model of AD. Using disease relevant single nucleotide variants (SNV), AD signaling and disease pathology was recapitulated in a neuronal model of AD. AGO increased MAP2, Tuj1, and Syn1 expression in this model confirming AGO’s neuroprotective mechanism of action.

Conclusions: I found that AGO exhibits sex-dependent effects in the TgF344-AD rat model. In females AGO preserved cognition and restored microglial activation to wildtype control levels while in males AGO decreased amyloid beta burden. In a human neuronal model of AD, AGO increased neuronal and synaptic integrity markers. Overall, these findings highlight AGO’s ability to mitigate AD related neurotoxicity, oxidative stress, and synaptic dysregulation.

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