Dissertations, Theses, and Capstone Projects

Date of Degree

9-2023

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor

Maria E. Figueiredo-Pereira

Committee Members

Patricia Rockwell

Peter Serrano

Gregory Elder

Jane A. Skok

Subject Categories

Animal Experimentation and Research | Molecular and Cellular Neuroscience | Other Genetics and Genomics | Translational Medical Research

Keywords

HDAC, HDACi, RG2833, Alzheimer, TgF344

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia. In the United States, AD affects about 6.2 million Americans and is projected to reach 13.8 million by 2050. Currently, there are no effective therapies for AD and therapies targeting epigenetic mechanisms have shown to be effective in improving cognitive performance in animal models of AD. However, until now no study has reported sex-dependent mechanisms leading to differential expression of genes that contribute to changes in AD pathology. From our in silico studies, we identified an FDA-approved drug, RG2833 (N-[6-(2-aminoanilino)-6-oxohexyl]-4-methylbenzamide) that penetrates the blood brain barrier and can potentially ameliorate AD pathology. This drug inhibits histone deacetylases (HDAC) 1 and 3 and exhibits both neuroprotective and anti-inflammatory properties. The overall GOAL of my studies was to understand the effects of HDAC inhibition on the neuromodulatory and neuroplasticity pathways relevant to AD. My central HYPOTHESIS was that inhibition of histone deacetylation activates neuroprotective genes to shield the brain from further neuronal damage and memory deficits in AD. The RATIONAL of my studies was that understanding the effects of HDAC inhibition on disease progression would advance the potential development of a new class of AD therapeutic agents. I tested my central hypothesis through the following specific aims with a transgenic rat model of AD (Chapter 1): Specific Aim 1: Determine the effects of HDAC 1/3 inhibition with RG2833 on spatial memory deficits and AD-like hippocampal pathology. Specific Aim 2: Determine the effects of HDAC 1/3 inhibition with RG2833 on gene expression in the hippocampus. Briefly, my studies investigated the long-term therapeutic effects of oral administration of a brain-penetrant HDAC1/3 inhibitor RG2833 in a Fisher transgenic 344-AD (TgF344-AD) rat model of AD. I show that there is no obvious toxicity on the TgF344-AD rats up to 6 months of treatment, starting at 5 months of age administering the drug in chow at ~30mg/kg of body weight. The drug treatment mitigated spatial memory deficits and significantly improved hippocampal-dependent spatial memory performance in TgF344-AD female but not male rats, compared to wild type littermates at 11 months of age. This female sex-specific drug effect has not been previously reported. RG2833 treatment failed to ameliorate amyloid beta accumulation and microgliosis in female TgF344-AD rats. Furthermore, RNAseq analysis of hippocampal tissue from TgF344-AD rats showed that drug treatment upregulated in females but not in males, the expression of immediate early genes, such as Arc, Egr1 and c-Fos, and other genes involved in synaptic plasticity and memory consolidation. These data indicate that histone modifying therapies can improve cognitive behavior by improving the expression of neuroprotective genes and by modulating synaptic plasticity. Based on my data, I propose that RG2833 could be an effective therapeutic to benefit female patients with AD.

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