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Effects of ibudilast treatment on hippocampal gene expression in Female Fisher transgenic 344-AD rats.

ABSTRACT: 5 month old Female Fisher transgenic 344-AD (Tg-AD) rats expressing humanSwedishamyloid precursor protein (APPsw) and Δ exon 9 presenelin-1 (PS1ΔE9) were treated with Ibudilast (cat. no. HY-B0763, MCE) at 10 mg/kg body weight administered in rodent chow. Following 6 months of Ibudilast treatment, rats (11 months of age) were tested for cognitive behaviour prior to sacrificing. Hippocampal Brain region were dissected and RNA sequencing (RNAseq) analyses was done on the Isolated sample. Taken together we showed that Ibudilast treatment: (i) reduces inflammation by decreasing the levels of the pro inflammatory cytokine IL6, interferon receptor 1, the macrophage migration inhibitory factor (MIF), microglial associated proteins such as transmembrane protein 119 (TMEM119), arachidonate 5-lipoxygenase activating protein (Alox5ap), toll like receptor 7 (TLR7), lysosomal protein transmembrane 5 (LAPTM5) and triggering receptor expressed on myeloid cells 2 (TREM2); (ii) increases expression of synaptic proteins such as synaptotagmin 2 (SYT2), which regulates vesicular transport, syntaxins (STX), which participates in neurotransmitter release, and cadherin (CDH1), which maintains synapse structure; and (iii) reduces the expression of the neurotrophic factor BDNF by 2-fold in both male and female treated rats.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE245623 | GEO | 2023/10/17

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 ibudilast treatment on hippocampal gene expression in Female Fisher transgenic 344-AD rats.

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