GNPS - Protein restriction slows the progression of Alzheimer's disease in a mouse model
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive
ORGANISM(S): Mus Musculus (ncbitaxon:10090)
SUBMITTER: 
John Denu
PROVIDER: MSV000094992 | GNPS | Tue Jun 11 12:18:00 BST 2024
REPOSITORIES: GNPS
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2024-06-11 | MSV000094992 | MassIVE
Project description:To identify molecular pathological alterations in AD brains, we performed interspecies comparative microarray analyses using RNAs prepared from postmortem human brain tissues donated for the Hisayama study and hippocampal RNAs from the triple-transgenic mouse model of AD (3xTg-AD) Three-way ANOVA of microarray data from frontal cortex, temporal cortex and hippocampus with presence/absence of AD and vascular dementia, and sex, as factors revealed that the gene expression profile is most significantly altered in the hippocampi of AD brains. Comparative analyses of the brains of AD patients and a mouse model of AD showed that genes involved in non-insulin dependent DM and obesity were significantly altered in both, as were genes related to psychiatric disorders and AlzheimerM-bM-^@M-^Ys disease. 3xTg-AD-H mice harboring a homozygous Psen1M146V mutation and homozygous mutant transgenes for APPSwe and tauP301L, 3xTg-AD-h mice harboring hemizygous APPSwe and tauP301L transgenes with a homozygous Psen1M146V mutation, and non-transgenic control mice (non-Tg) were used in this study, (male, n=3 for each group). RNA samples prepared from hippocampi were subjected to microarray analysis using the Affymetrix Mouse Gene 1.0 ST platform (GPL6246).
2013-04-17 | E-GEOD-36981 | biostudies-arrayexpress
Project description:To identify molecular pathological alterations in AD brains, we performed interspecies comparative microarray analyses using RNAs prepared from postmortem human brain tissues donated for the Hisayama study and hippocampal RNAs from the triple-transgenic mouse model of AD (3xTg-AD) Three-way ANOVA of microarray data from frontal cortex, temporal cortex and hippocampus with presence/absence of AD and vascular dementia, and sex, as factors revealed that the gene expression profile is most significantly altered in the hippocampi of AD brains. Comparative analyses of the brains of AD patients and a mouse model of AD showed that genes involved in non-insulin dependent DM and obesity were significantly altered in both, as were genes related to psychiatric disorders and Alzheimer’s disease.
2013-04-17 | GSE36981 | GEO
Project description:Alzheimer's disease (AD) is a chronic neurological disease which characterized as memory loss and progressive cognitive impairment. The characteristic of AD pathologies include extracellular senile plaques formed by β-amyloid protein deposition, neurofifibrillary tangles formed byhyper-phosphorylation of tau protein, and neuronal loss caused by glial cell proliferation. However, the pathogenesis of AD is still unclear. Resent research have shown that the dysregulation of RNA methylation is related to many biological processes, including neurodevelopment and neurodegenerative diseases. N6-methyladenosine (m6A) is the mainly modification in eukaryotic RNA, and it may be associated with the pathophysiology of AD. Circular RNA (circRNA) is a new type of evolutionarily conserved non-coding RNA without 5’cap and 3’polyadenylic acid tail. Recent studies suggested that circRNA may involved in the pathogenesis of AD. m6A RNA methylation is also found in circRNAs. In this study, we performed high-throughput sequencing on the degree of circRNA m6A methylation in APP/PS1 AD and C57BL/6 mice. The results suggest that circRNA m6A methylation degree in AD mice is different compared to the control group. In addition, using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to predict related pathways, the results showed that the genes with different circRNA m6A methylation in AD mice is associated with axon guidance, long-term potentiation, glutama tergic synapse, cholinergic synapse, gabaergic synapse and long-term depression. The MeRIP-qPCR results showed that among the 8 selected circRNA m6A genes, there are 5 genes with increased methylation and others with decreased methylation. In summary, the results of this study indicate that circRNA m6A methylation may related to the pathogenesis of AD.
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Project description:Alzheimer’s disease (AD) is a neurodegenerative disease displaying plaques formed by the neurotoxic amyloid β-peptide (Aβ) and intracellular neurofibrillary tangles consisting of protein tau. However, how these pathologies relates to the massive neuronal death that occurs in AD brains remain elusive. To identify proteins, the levels of which are affected by increased Aβ levels, we performed a proteomic analysis of the AD mouse model APPsw and compared it to that of APPsw mice lacking the major Aβ degrading enzyme neprilysin. This was achieved by establishing an LC-MS/MS method to analyze brain homogenate, using an 18O-labeled internal standard to accurately quantify the protein levels. By this approach we identified approximately 600 proteins and could quantify the levels of 300 of these. Interestingly, several proteins, including some not previously reported to be associated with AD, were identified. The relevance of these proteins for AD warrants further research.
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Project description:Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-beta (Ab) plaques and neurofibrillary tangles, neuroinflammation, and glial activation. Asrij/OCIAD1 (Ovarian Carcinoma Immunoreactive Antigen Domain containing protein 1) is an AD-associated factor. Increased Asrij levels in the brains of AD patients and mouse models are linked to the severity of neurodegeneration. However, the contribution of Asrij to AD progression and whether reducing Asrij levels is sufficient to mitigate Ab pathology in vivo is unclear. To explore the impact of Asrij on AD pathology, we deleted asrij in the APP/PS1 mouse model of AD and analyzed the effects on AD hallmarks. We find that Asrij depletion ameliorates cognitive impairments, Ab deposition, neuronal and synaptic damage, and reactive astrogliosis in the AD mouse. Emerging evidence indicates a critical role of microglia in influencing AD pathology. Notably, Asrij-deficient microglia exhibit reduced plaque-associated proliferation and decreased phagocytic activity. Transcriptomic analyses of AD microglia reveal upregulation of energy metabolism pathways and downregulation of innate immunity and inflammatory pathways upon Asrij depletion. Mechanistically, loss of Asrij increases mitochondrial activity and Akt/mTOR signaling and impedes the pro-inflammatory Disease-Associated Microglia (DAM) state. Reduced levels of pro-inflammatory cytokines and decreased STAT3 and NF-kB activation indicate protective changes in AD microglia. Taken together, our results suggest that increased Asrij levels reported in AD, may suppress microglial metabolic activity and promote inflammatory microglial activation, thereby exacerbating AD pathology. Our study establishes a novel role for Asrij in regulating microglial responses to Ab pathology, and could be a potential target for therapeutic intervention.
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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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