Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of human Alzheimers disease patients to identify genes regulating synaptic function and neuroplasticity in incipient AD

ABSTRACT: In Alzheimer's disease (AD), early deficits in learning and memory are a consequence of synaptic modification which are likely induced by toxic beta-amyloid oligomers (dAbeta). To identify molecular targets downstream of dAbeta binding we prepared synaptoneurosomes from frontal cortex of control and IAD patients, and isolated mRNAs for comparison of gene expression. This approach elevated synaptic mRNAs above the threshold necessary for expression changes to be discriminated and also reduced other cellular mRNAs. In patients with minimal cognitive impairment (MCI) termed incipient AD (IAD) global measures of cognition declined with increasing levels of dimeric beta (dAbeta). These patients also showed increased expression of neuroplasticity related genes, many encoding 3' UTR consensus sequences that regulate local translation in the synapse. One such gene, GluR2, displayed elevated mRNA and protein expression in IAD. Other neurotransmitter-related genes were also upregulated. Overexpressed genes may induce compensatory as well as negative effects on cognition and provide targets for intervention to moderate the response to dAbeta. Experiment Overall Design: Patient information Experiment Overall Design: CNS tissues were obtained from the USC Alzheimer's Disease Research Center (ADRC) Neuropathology Core, NIA AG05142. Clinical information, including neurological examination, neuropsychological testing such as cognitive assessment, family history, and medications were provided by the USC ADRC Clinical Core. The groups did not differ significantly in age or years of education. Medication histories indicated one IAD patient had used a selective serotonin uptake inhibitor. Post-mortem interval (PMI) ranged from 2 to 9 hours (mean 5.1 hrs.). The study included 8 normal controls and 6 patients with Incipient Alzheimer's Disease. Experiment Overall Design: To augment studies comparing homogenates of control to AD brains, we used synaptoneurosome preparations to enrich for synaptic mRNAs. Synaptoneurosomes were prepared from the prefrontal cortices of control and IAD patients by a simple, rapid, but gentle method using sequential mesh screens.

ORGANISM(S): Homo sapiens

SUBMITTER: Celia Williams

PROVIDER: E-GEOD-12685 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Transcriptome analysis of synaptoneurosomes identifies neuroplasticity genes overexpressed in incipient Alzheimer's disease.

Williams Celia C Mehrian Shai Ruty R Wu Yongchun Y Hsu Ya-Hsuan YH Sitzer Traci T Spann Bryan B McCleary Carol C Mo Yi Y Miller Carol A CA

PloS one 20090319 3

In Alzheimer's disease (AD), early deficits in learning and memory are a consequence of synaptic modification induced by toxic beta-amyloid oligomers (oAbeta). To identify immediate molecular targets downstream of oAbeta binding, we prepared synaptoneurosomes from prefrontal cortex of control and incipient AD (IAD) patients, and isolated mRNAs for comparison of gene expression. This novel approach concentrates synaptic mRNA, thereby increasing the ratio of synaptic to somal mRNA and allowing dis ...[more]

PMID: 19295912

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Project description:Action of alcohol on synaptic mRNA in the amygdala of mice Chronic alcohol consumption induces changes in gene expression, causing persistent long-term neuro-adaptations and the remodeling of synaptic structures. These alcohol-induced synaptic changes may rely specifically on the local translation of mRNAs in the synaptic compartments of the cell. We profiled the transcriptome from synaptoneurosomes (SN) and paired total homogenates (TH) of amygdala to analyze the synaptic adaptations induced by chronic voluntary alcohol consumption in mice. In the SN both the number of alcohol-responsive mRNAs and the magnitude of fold-change were greater than in the TH. Accordingly, the SN detected many genes with coordinated patterns of expression producing a highly connected mRNA network in gene co-expression analysis. The greater sensitivity of the SN preparation allowed for improved cell-type specificity analysis, revealing an up-regulation of alcohol-responsive astrocytic and microglial modules that correlated with alcohol consumption. Alcohol was found to induce changes in the SN functionally important biological pathways, including long-term potentiation, long-term potentiation depression, glutamate pathway, neuro-immune, RNA-processing and translational machineries and provided overlap with changes seen in human alcoholic brain. Transposable elements were responsive to alcohol and found in the down-regulated neuronal mRNA module, which may underlie some of the coordinated gene expression changes associated with alcohol. We provide evidence that enrichment of synaptic components reveals a more intricate network of coordinated gene expression. Increased resolution captures the molecular effects of synaptic manipulations and provides an improved technique for identifying therapeutic targets for alcohol abuse. Local translation of mRNAs in the synapse plays a major role in synaptic structure and function. Chronic alcohol use causes persistent changes in synaptic mRNA expression, possibly mediated by microRNAs localized in the synapse. We profiled the transcriptome of synaptoneurosomes (SN) from the amygdala of mice chronically consuming 20% ethanol in a continuous two-bottle choice test to identify the microRNAs that target alcohol-induced mRNAs. SN are membrane vesicles containing pre- and post-synaptic compartments of neurons and astroglia and are a unique model for studying the synaptic transcriptome. We previously showed that chronic alcohol regulates mRNA expression in a coordinated manner. Here, we examine microRNAs and mRNAs from the same samples to define alcohol-responsive synaptic microRNAs and their predicted interactions with targeted mRNAs. We used a combination of unbiased bioinformatic methods (differential expression, correlation, co-expression, microRNA-mRNA target prediction, co-targeting and cell type specific analyses) to identify key alcohol-sensitive microRNAs. Bidirectional mRNA-microRNA prediction analysis showed that a subset of alcohol-responsive microRNAs were predicted to target many alcohol-responsive mRNAs. We found microRNAs-mRNAs with overlapping patterns of expression that correlated with the amount of alcohol consumed. Cell-type specific analysis revealed a significant number of the alcohol-responsive mRNAs and microRNAs that were unique to glutamate neurons and were highly predicted to target each other. Chronic alcohol appears to perturb the coordinated microRNA regulation of mRNAs in SN, a mechanism that may explain the aberrations in synaptic plasticity affecting the alcoholic brain.

Dataset Information

Transcription profiling of human Alzheimers disease patients to identify genes regulating synaptic function and neuroplasticity in incipient AD

Publications

Transcriptome analysis of synaptoneurosomes identifies neuroplasticity genes overexpressed in incipient Alzheimer's disease.

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