Dissertations, Theses, and Capstone Projects

Date of Degree

9-2024

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor

Maria Figueiredo-Pereira

Committee Members

Patricia Rockwell

Peter Serrano

Claire Henchcliffe

Marta Olah

Subject Categories

Biology | Disease Modeling | Molecular and Cellular Neuroscience

Keywords

LANCL2, BT-11

Abstract

Approximately 99.6% of potential Alzheimer’s drugs fail, thus developing successful drugs is a high priority. The failure at developing successful drugs relates to the complex nature of the disease itself. Many components act together to trigger a cascade that ultimately results in neurodegeneration and cognitive dysfunction associated with the disease. In building a multiplex model of Alzheimer’s it is important to understand its specific biological mechanisms. One of these key pathological mechanisms is neuroinflammation. Understanding the pathways involved in neuroinflammation in Alzheimer’s is an urgent need, as it poses a promising avenue for future effective therapeutics. Specifically, as many investigational and FDA approved drugs targeting inflammation already exist, repurposing drugs is a useful approach, and this avenue provides for a less expensive and quicker process than developing new pharmaceuticals.

One of such drugs is BT-11, which is an orally active lanthionine synthetase C-like 2 (LANCL2) binding compound, shown to reduce inflammation in the gut and improve cognitive function. Additionally, LANCL2 was identified as a glutathione-s-transferase, suggesting a role in removing toxins and reducing oxidative stress. BT-11 was predicted to have potential to treat Alzheimer’s, based on in silico studies for drug repurposing.

The overall GOAL of my studies was to explore the potential of the investigational drug BT-11 and its mechanisms to treat Alzheimer’s. My central hypothesis was that activation of the LANCL2 pathway with BT-11 prevents or diminishes the progression of Alzheimer’s. The RATIONALE of my studies was that understanding the effects and mechanisms by which BT-11 potentially prevents or diminishes disease progression, will advance the development of novel therapeutics and their target, LANCL2, to treat Alzheimer’s.

The results of my studies to test the central hypothesis are addressed in the following chapters:

1. BT-11 treatment alleviates cognitive deficits and pathology in a sex-specific manner in a rat Alzheimer’s model (chapter 2)

I showed that long-term treatment with BT-11 reduced hippocampal-dependent spatial memory deficits, as well as Aβ plaque load and neuronal loss in the dorsal hippocampus of TgF344-AD male rats compared to WT rats. While these effects were not observed in female TgF344-AD rats, BT-11 treatment mitigated microglia numbers in the dorsal hippocampus of TgF344-AD female rats compared to WT rats.

2. Potential mechanisms mediating the effects of the LANCL2 activator BT-11 in a rat Alzheimer’s model (chapter 3)

I showed that BT-11 potentially crosses the blood brain barrier. Moreover, through RNAseq analyses, I determined that treatment with BT-11 leads to changes in the signaling receptor and G-protein signaling receptor pathways, pointing to probable mechanisms mediating BT-11 action.

I also found that, in the dorsal hippocampus, LANCL2 is present in the intracellular nuclear and cytoplasmic fractions with different post-translational modifications, suggesting distinct functions based on subcellular location. Interestingly, I established that LANCL2 is present in dorsal hippocampal oligodendrocytes. The study of the role of oligodendrocytes in Alzheimer’s is ongoing and my finding suggests that the LANCL2 pathway could play a role. To my knowledge, these last findings are novel as they have not been previously reported.

Overall, my data suggest that targeting LANCL2 with BT-11 can improve cognition and reduce pathological hallmarks by modulating G-protein signaling and potentially oligodendrocyte function in Alzheimer’s. My study provides a significant contribution to the field of novel immunomodulatory targets for Alzheimer’s therapeutics and merits further research on the role of LANCL2 in the disease.

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