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Altered neuronal gene expression in brain regions differentially affected by Alzheimer's disease: a reference data set.

ABSTRACT: Alzheimer's Disease (AD) is the most widespread form of dementia during the later stages of life. If improved therapeutics are not developed, the prevalence of AD will drastically increase in the coming years as the world's population ages. By identifying differences in neuronal gene expression profiles between healthy elderly persons and individuals diagnosed with AD, we may be able to better understand the molecular mechanisms that drive AD pathogenesis, including the formation of amyloid plaques and neurofibrillary tangles. In this study, we expression profiled histopathologically normal cortical neurons collected with laser capture microdissection (LCM) from six anatomically and functionally discrete postmortem brain regions in 34 AD-afflicted individuals, using Affymetrix Human Genome U133 Plus 2.0 microarrays. These regions include the entorhinal cortex, hippocampus, middle temporal gyrus, posterior cingulate cortex, superior frontal gyrus, and primary visual cortex. This study is predicated on previous parallel research on the postmortem brains of the same six regions in 14 healthy elderly individuals, for which LCM neurons were similarly processed for expression analysis. We identified significant regional differential expression in AD brains compared with control brains including expression changes of genes previously implicated in AD pathogenesis, particularly with regard to tangle and plaque formation. Pinpointing the expression of factors that may play a role in AD pathogenesis provides a foundation for future identification of new targets for improved AD therapeutics. We provide this carefully phenotyped, laser capture microdissected intraindividual brain region expression data set to the community as a public resource.

SUBMITTER: Liang WS

PROVIDER: S-EPMC2826117 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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Altered neuronal gene expression in brain regions differentially affected by Alzheimer's disease: a reference data set.

Liang Winnie S WS Dunckley Travis T Beach Thomas G TG Grover Andrew A Mastroeni Diego D Ramsey Keri K Caselli Richard J RJ Kukull Walter A WA McKeel Daniel D Morris John C JC Hulette Christine M CM Schmechel Donald D Reiman Eric M EM Rogers Joseph J Stephan Dietrich A DA

Physiological genomics 20080212 2

Alzheimer's Disease (AD) is the most widespread form of dementia during the later stages of life. If improved therapeutics are not developed, the prevalence of AD will drastically increase in the coming years as the world's population ages. By identifying differences in neuronal gene expression profiles between healthy elderly persons and individuals diagnosed with AD, we may be able to better understand the molecular mechanisms that drive AD pathogenesis, including the formation of amyloid plaq ...[more]

PMID: 18270320

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Project description:BackgroundAlzheimer's disease (AD) is the most common form of dementia in older adults that damages the brain and results in impaired memory, thinking and behaviour. The identification of differentially expressed genes and related pathways among affected brain regions can provide more information on the mechanisms of AD. In the past decade, several studies have reported many genes that are associated with AD. This wealth of information has become difficult to follow and interpret as most of the results are conflicting. In that case, it is worth doing an integrated study of multiple datasets that helps to increase the total number of samples and the statistical power in detecting biomarkers. In this study, we present an integrated analysis of five different brain region datasets and introduce new genes that warrant further investigation.MethodsThe aim of our study is to apply a novel combinatorial optimisation based meta-analysis approach to identify differentially expressed genes that are associated to AD across brain regions. In this study, microarray gene expression data from 161 samples (74 non-demented controls, 87 AD) from the Entorhinal Cortex (EC), Hippocampus (HIP), Middle temporal gyrus (MTG), Posterior cingulate cortex (PC), Superior frontal gyrus (SFG) and visual cortex (VCX) brain regions were integrated and analysed using our method. The results are then compared to two popular meta-analysis methods, RankProd and GeneMeta, and to what can be obtained by analysing the individual datasets.ResultsWe find genes related with AD that are consistent with existing studies, and new candidate genes not previously related with AD. Our study confirms the up-regualtion of INFAR2 and PTMA along with the down regulation of GPHN, RAB2A, PSMD14 and FGF. Novel genes PSMB2, WNK1, RPL15, SEMA4C, RWDD2A and LARGE are found to be differentially expressed across all brain regions. Further investigation on these genes may provide new insights into the development of AD. In addition, we identified the presence of 23 non-coding features, including four miRNA precursors (miR-7, miR570, miR-1229 and miR-6821), dysregulated across the brain regions. Furthermore, we compared our results with two popular meta-analysis methods RankProd and GeneMeta to validate our findings and performed a sensitivity analysis by removing one dataset at a time to assess the robustness of our results. These new findings may provide new insights into the disease mechanisms and thus make a significant contribution in the near future towards understanding, prevention and cure of AD.

Project description:BackgroundAlzheimer's disease and vascular cognitive impairment (VCI), as well as their concurrence, represent the most common types of cognitive dysfunction. Treatment strategies for these two conditions are quite different; however, there exists a considerable overlap in their clinical manifestations, and most biomarkers reveal similar abnormalities between these two conditions.PurposeTo evaluate the potential of cerebral oxygen extraction fraction (OEF) as a biomarker for differential diagnosis of Alzheimer's disease and VCI. We hypothesized that in Alzheimer's disease OEF will be reduced (decreased oxygen consumption due to decreased neural activity), while in vascular diseases OEF will be elevated (increased oxygen extraction due to abnormally decreased blood flow).Study typeProspective cross-sectional.PopulationSixty-five subjects aged 52-89 years, including 33 mild cognitive impairment (MCI), 7 dementia, and 25 cognitively normal subjects.Field strength/sequence3T T2 -relaxation-under-spin-tagging (TRUST) and fluid-attenuated inversion recovery imaging (FLAIR).AssessmentOEF, consensus diagnoses of cognitive impairment, vascular risk factors (such as hypertension, hypercholesterolemia, diabetes, smoking, and obesity), cognitive assessments, and cerebrospinal fluid concentration of amyloid and tau were assessed.Statistical testsMultiple linear regression analyses of OEF with diagnostic category (normal, MCI, or dementia), vascular risks, cognitive performance, amyloid and tau pathology.ResultsWhen evaluating the entire group, OEF was found to be lower with more severe cognitive impairment (β = -2.70 ± 1.15, T = -2.34, P = 0.02), but was higher with greater vascular risk factors (β = 1.36 ± 0.55, T = 2.48, P = 0.02). Further investigation of the subgroup of participants with low vascular risks (N = 44) revealed that lower OEF was associated with worse cognitive performance (β = 0.04 ± 0.01, T = 3.27, P = 0.002) and greater amyloid burden (β = 92.12 ± 41.23, T = 2.23, P = 0.03). Among cognitively impaired individuals (N = 40), higher OEF was associated with greater vascular risk factors (β = 2.19 ± 0.71, T = 3.08, P = 0.004).Data conclusionThese findings suggest that OEF is differentially affected by Alzheimer's disease and VCI pathology and may be useful in etiology-based diagnosis of cognitive impairment.Level of evidence1 TECHNICAL EFFICACY: Stage 3 J. MAGN. RESON. IMAGING 2020;52:1829-1837.

Project description:BackgroundPUFAs play vital roles in the development, maintenance, and functioning of circuitries that regulate reward and social behaviors. Therefore, modulations in PUFA concentrations of these brain regions may disrupt reward and social circuitries contributing to mood disorders, developmental disabilities, and addictions. Though much is known about regional and phospholipid-pool-specific PUFA concentrations, less is known about the effects of dietary interventions that concurrently lowers n-6 PUFA and supplements n-3 PUFA, on brain PUFA concentrations. There is even less knowledge on the effects of sex on brain PUFA concentrations.ObjectiveThis study aimed to comprehensively examine the interaction effects of diet (D), sex (S), brain regions (BR), and phospholipid pools (PL) on brain PUFA concentrations.MethodsMale and female C57BL/6J mice were fed 1 of 4 custom-designed diets varying in linoleic acid (LNA) (8 en% or 1 en%) and eicosapentaenoic acid/docosahexaenoic acid (EPA/DHA) (0.4 en% or 0 en%) concentrations from in utero to 15 weeks old. At 15 weeks old, the prefrontal cortex, dorsal striatum, and cerebellum were collected. Fatty acids of 5 major PL were quantified by GC-flame ionization detection. Repeated measures ANOVA was used to test for differences among the groups for D, S, BR, and PL.ResultsNo significant 4-way interactions on PUFA concentrations. DHA, predominant n-3 PUFA, concentrations were dependent on significant D × BR × PL interactions. DHA concentration was not affected by sex. Arachidonic acid (ARA; predominant n-6 PUFA) concentrations were not dependent on 3-way interactions. However, significant 2-way D × PL, BR × PL, and D × Sinteractions affected ARA concentrations. Brain fatty acid concentrations were differentially affected by various combinations of D, S, BR, and PL interactions.ConclusionThough DHA concentrations are not affected by sex, ARA concentrations are affected by interactions of the 4 variables examined. This study provides comprehensive references in the investigation of complex interactions between factors that affect brain PUFA concentrations in mice.

Dataset Information

Altered neuronal gene expression in brain regions differentially affected by Alzheimer's disease: a reference data set.

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Altered neuronal gene expression in brain regions differentially affected by Alzheimer's disease: a reference data set.

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