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Effects of RG2833 (HDAC1/3 Inhibitor) on the gene expression of Female TgF344 Alzheimer’s disease Rat model.

ABSTRACT: We 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) rats model of AD. We treated for 6 months, starting at 5 months of age administering the drug in rodent chow at ~30mg/kg of body weight. After treatment we performed experiements to show the effects of drug treatment on spatial memory deficits. We show significantly improved hippocampal-dependent spatial memory performance in TgF344-AD female.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE247141 | GEO | 2024/10/27

REPOSITORIES: GEO

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Project description:Alzheimer's disease (AD) is the most common form of dementia. Obesity in middle age increases AD risk and severity, which is alarming given that obesity prevalence peaks at middle age and obesity rates are accelerating worldwide. Midlife, but not late-life obesity increases AD risk, suggesting that this interaction is specific to preclinical AD. AD pathology begins in middle age, with accumulation of amyloid beta (Aβ), hyperphosphorylated tau, metabolic decline, and neuroinflammation occurring decades before cognitive symptoms appear. We used a transcriptomic discovery approach in young adult (6.5 months old) male and female TgF344-AD rats that overexpress mutant human amyloid precursor protein and presenilin-1 and wild-type (WT) controls to determine whether inducing obesity with a high-fat/high-sugar “Western” diet during preclinical AD increases brain metabolic dysfunction in dorsal hippocampus (dHC), a brain region vulnerable to the effects of obesity and early AD. Analyses of dHC gene expression data showed dysregulated mitochondrial and neurotransmission pathways, and up-regulated genes involved in cholesterol synthesis. Western diet amplified the number of genes that were different between AD and WT rats and added pathways involved in noradrenergic signaling, dysregulated inhibition of cholesterol synthesis, and decreased intracellular lipid transporters. Importantly, the Western diet impaired dHC-dependent spatial working memory in AD but not WT rats, confirming that the dietary intervention accelerated cognitive decline. To examine later consequences of early transcriptional dysregulation, we measured dHC monoamine levels in older (13 months old) AD and WT rats of both sexes after long-term chow or Western diet consumption. Norepinephrine (NE) abundance was significantly decreased in AD rats, NE turnover was increased, and the Western diet attenuated the AD-induced increases in turnover. Collectively, these findings indicate obesity during prodromal AD impairs memory, potentiates AD-induced metabolic decline likely leading to an overproduction of cholesterol, and interferes with compensatory increases in NE transmission.

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Effects of RG2833 (HDAC1/3 Inhibitor) on the gene expression of Female TgF344 Alzheimer’s disease Rat model.

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