Basal forebrain cholinergic neurons are vulnerable in a mouse model of Down syndrome and their molecular fingerprint is rescued by maternal choline supplementation
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ABSTRACT:
PROVIDER: PRJNA1032114 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26525600.fastq.gz | Fastqsanger.gz | |||
| SRR26525601.fastq.gz | Fastqsanger.gz | |||
| SRR26525602.fastq.gz | Fastqsanger.gz | |||
| SRR26525603.fastq.gz | Fastqsanger.gz | |||
| SRR26525604.fastq.gz | Fastqsanger.gz |
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Project description:Basal forebrain cholinergic neuron (BFCN) degeneration is a hallmark of Down syndrome (DS) and Alzheimer's disease (AD). Current therapeutics in these disorders have been unsuccessful in slowing disease progression, likely due to poorly understood complex pathological interactions and dysregulated pathways. The Ts65Dn trisomic mouse model recapitulates both cognitive and morphological deficits of DS and AD, including BFCN degeneration and has shown lifelong behavioral changes due to maternal choline supplementation (MCS). To test the impact of MCS on trisomic BFCN, we performed laser capture microdissection to individually isolate choline acetyltransferase-immunopositive neurons in Ts65Dn and disomic littermates, in conjunction with MCS at the onset of BFCN degeneration. We utilized single population RNA sequencing (RNA-seq) to interrogate transcriptomic changes within medial septal nucleus (MSN) BFCN. Leveraging multiple bioinformatic analysis programs on differentially expressed genes (DEGs) by genotype and diet, we identified key canonical pathways and altered physiological functions within Ts65Dn MSN BFCN, which were attenuated by MCS in trisomic offspring, including the cholinergic, glutamatergic and GABAergic pathways. We linked differential gene expression bioinformatically to multiple neurological functions, including motor dysfunction/movement disorder, early onset neurological disease, ataxia and cognitive impairment via Ingenuity Pathway Analysis. DEGs within these identified pathways may underlie aberrant behavior in the DS mice, with MCS attenuating the underlying gene expression changes. We propose MCS ameliorates aberrant BFCN gene expression within the septohippocampal circuit of trisomic mice through normalization of principally the cholinergic, glutamatergic, and GABAergic signaling pathways, resulting in attenuation of underlying neurological disease functions.
2023-10-30 | GSE246245 | GEO
Project description:Down syndrome (DS) stemming from triplication of chromosome 21 causes intellectual disability, with early onset of Alzheimer’s disease (AD) pathology in mid-life. Early intervention studies to reduce cognitive impairments and onset of pathology are lacking. One such treatment, maternal choline supplementation (MCS), has shown beneficial effects on behavior and gene expression in neurodegenerative and neurodevelopmental diseases in rodent models including DS mouse models. Basal forebrain cholinergic neuron (BFCN) degeneration and enlarged endosomal phenotype is reduced due to maternal choline supplementation (MCS) in a mouse model of Down Syndrome (Ts65Dn) with concomitant beneficial behavioral effects. However, the underlying mechanisms and gene expression alterations during aging and BFCN degeneration are understudied. We postulate cellular mechanisms driving these alterations will be elucidated with novel therapeutic targets identified by examining the modulation in MCS treated aged DS mice. Immunohistochemical ChAT staining in the medial septal/ventral diagonal band area of the basal forebrain in ~11 MO DS and control (2N) mice with and without MCS was performed. Approximately 500 cholinergic positive neurons per animal were microisolated for RNA-sequencing. Bioinformatic analysis elucidated gene expression alterations in the aged DS mouse model compared to controls which were attenuated by MCS treatment in the DS and control animals, including cognitive impairment and NAD signaling pathway. In conclusion, MCS treatment shows moderate effects on gene expression in aged BFCNs, indicating that MCS prolongs the healthspan in this DS mouse model, but does not eliminate disease onset.
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Project description:Gene expression was compared from adult C. elegans after RNAi Triplicate control RNAi (Empty vector), control RNAi, choline treated, sams-1(RNAi) and sams-1(RNAi) choline treated animals were grown to young adulthood and RNA was extracted
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Project description:Acetylcholine (ACh) and its receptors (AChRs) are widely produced by various kinds of immune cells and fine-tune both innate and adaptive immune responses. However, whether cholinergic signaling regulates immune cell development is unclear. Here, we show that mouse CD4+CD8+ double-positive (DP) thymocytes express high levels of a9 nicotinic (n) AChR, and that this receptor controls the negative selection of thymocytes. Knock-out mice lacking a9 nAChR show an altered TCR repertoire and reduced CD4+ and CD8+ T cells in a mixed bone marrow chimera setting. Although thymic tuft cells, B cells, and a portion of T cells were all found to express choline acetyltransferase (ChAT) and so are sources of ACh in mouse thymus, T cell-derived ACh plays a more important regulatory role. Our results thus reveal a new mechanism of immune cell development control that involves lymphocyte-mediated cholinergic signaling.
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Project description:Eubacterium limosum ATCC 8486 makes acetate and butyrate from various substrates and is found in the human intestine. The proteome of choline -grown Eubacterium limosum was obtained in order to identify enzymes required for growth on choline, in particular to identify components that are unique to growth on choline in comparison to other substrates for acetogenesis, such as lactic acid, L-carnitine, or proline betaine. Choline is converted to trimethylamine (TMA) by certain members of the gut microbiome. Subsequent liver metabolism of TMA is now tied to progression of cardiovascular disease. Demethylation of choline is observed during growth of Eubacterium limosum on this substrate, and does not produce TMA. Choline demethylation by organisms like Eubacterium limosum could lessen TMA production in the gut, thereby lessening the propensity towards atherosclerosis caused by metabolism of TMA in the body. This proteome led to discovery of a phosphocholine:tetrahydrofolate methyltransferase system. The key choline demethylating enzyme is a member of the widespread TMA methyltransferase protein superfamily.
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Project description:Choline and methionine/choline deficient diets are widely used to generate severe rodent hepatic steatosis and steatohepatitis in an attempt to reflect stages of human non-alcoholic fatty liver disease (NAFLD). The underlying mechanism of hepatic injury in these models, and how this reflects human disease remains incompletely understood. We used detailed transcriptional analysis to interrogate the molecular mechanisms of this intervention and its similarity to human disease. Adult C57Bl/6J mice were maintained on control, choline deficient (CDD) or methionine/choline deficient (MCDD) diets for 4 weeks. Isolated liver RNA was used for transcriptional profiling by micro array analysis.
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Project description:To explore the influence of maternal choline intake on placental gene expression, we employed whole genome microarray expression profiling to identify genes that were differentially expressed in placental tissues obtained from women consuming two different doses (480 vs. 930 mg/d) of choline throughout the third trimester of pregnancy. Healthy third trimester (gestational week 26-29) pregnant women were randomized to a 12-week choline controlled feeding study. The participants consumed either 480 (n=6) or 930 (n=6) mg choline/d. Full thickness placental samples were collected at delivery to extract RNA and perform the arrays. Healthy third trimester (gestational week 26-29) pregnant women were randomized to a 12-week choline controlled feeding study. The participants consumed either 480 (n=6) or 930 (n=6) mg choline/d for 12 weeks. Placental samples were obtained at delivery
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