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Brain gene expression patterns differentiate mild cognitive impairment from normal aged and Alzheimer's disease.
Neurobiol Aging. 2014 Sep; 35(9):1961-72.NA

Abstract

Mild cognitive impairment (MCI) represents a cognitive state intermediate between normal aging and early Alzheimer's disease (AD). To investigate if the molecular signature of MCI parallels the clinical picture, we use microarrays to extensively profile gene expression in 4 cortical brain regions (entorhinal cortex, hippocampus, superior frontal gyrus, post-central gyrus) using the postmortem tissue from cognitively normal aged controls, MCI, and AD cases. Our data reveal that gene expression patterns in MCI are not an extension of aging, and for the most part, are not intermediate between aged controls and AD. Functional enrichment analysis of significant genes revealed prominent upregulation in MCI brains of genes associated with anabolic and biosynthetic pathways (notably transcription, protein biosynthesis, protein trafficking, and turnover) as well as mitochondrial energy generation. In addition, many synaptic genes showed altered expression in MCI, predominantly upregulation, including genes for central components of the vesicle fusion machinery at the synapse, synaptic vesicle trafficking, neurotransmitter receptors, and synaptic structure and stabilization. These data suggest that there is a rebalancing of synaptic transmission in the MCI brain. To investigate if synaptic gene expression levels in MCI were related to cognitive function, Pearson correlation coefficient between the Mini Mental State Examination (MMSE) and region-specific messenger RNA expression were computed for MCI cases. A number of synaptic genes showed strong significant correlations (r > 0.8, p < 0.01) most notably in the entorhinal cortex, with fewer in the hippocampus, and very few in neocortical regions. The synaptic genes with highly significant correlations were predominantly related to synaptic transmission and plasticity, and myelin composition. Unexpectedly, we found that gene expression changes that facilitate synaptic excitability and plasticity were overwhelmingly associated with poorer MMSE, and conversely that gene expression changes that inhibit plasticity were positively associated with MMSE. These data suggest that there are excessive excitability and apparent plasticity in limbic brain regions in MCI, that is associated with impaired synaptic and cognitive function. Such changes would be predicted to contribute to increased excitability, in turn leading to greater metabolic demand and ultimately progressive degeneration and AD, if not controlled.

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Authors+Show Affiliations

Berchtold NC
Institute for Mental Impairments and Neurological Disorders (MIND), University of California Irvine, Irvine, CA, USA. Electronic address: nberchto@uci.edu.
Sabbagh MN
Banner Sun Health Research Institute, Sun City, AZ, USA.
Beach TG
Banner Sun Health Research Institute, Sun City, AZ, USA.
Kim RC
Institute for Mental Impairments and Neurological Disorders (MIND), University of California Irvine, Irvine, CA, USA.
Cribbs DH
Institute for Mental Impairments and Neurological Disorders (MIND), University of California Irvine, Irvine, CA, USA; Departments of Neurology and Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA.
Cotman CW
Institute for Mental Impairments and Neurological Disorders (MIND), University of California Irvine, Irvine, CA, USA; Departments of Neurology and Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA.

MeSH

AgedAged, 80 and overAgingAlzheimer DiseaseBrainCognitive DysfunctionEnergy MetabolismFemaleGene ExpressionGene Expression ProfilingHumansMaleMetabolismMicroarray AnalysisMitochondriaMyelin SheathNeuronal PlasticityNeuropsychological TestsProtein BiosynthesisProtein TransportSynaptic TransmissionTranscription, Genetic

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

24786631

Citation

Berchtold, Nicole C., et al. "Brain Gene Expression Patterns Differentiate Mild Cognitive Impairment From Normal Aged and Alzheimer's Disease." Neurobiology of Aging, vol. 35, no. 9, 2014, pp. 1961-72.
Berchtold NC, Sabbagh MN, Beach TG, et al. Brain gene expression patterns differentiate mild cognitive impairment from normal aged and Alzheimer's disease. Neurobiol Aging. 2014;35(9):1961-72.
Berchtold, N. C., Sabbagh, M. N., Beach, T. G., Kim, R. C., Cribbs, D. H., & Cotman, C. W. (2014). Brain gene expression patterns differentiate mild cognitive impairment from normal aged and Alzheimer's disease. Neurobiology of Aging, 35(9), 1961-72. https://doi.org/10.1016/j.neurobiolaging.2014.03.031
Berchtold NC, et al. Brain Gene Expression Patterns Differentiate Mild Cognitive Impairment From Normal Aged and Alzheimer's Disease. Neurobiol Aging. 2014;35(9):1961-72. PubMed PMID: 24786631.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Brain gene expression patterns differentiate mild cognitive impairment from normal aged and Alzheimer's disease. AU - Berchtold,Nicole C, AU - Sabbagh,Marwan N, AU - Beach,Thomas G, AU - Kim,Ronald C, AU - Cribbs,David H, AU - Cotman,Carl W, Y1 - 2014/04/02/ PY - 2013/12/19/received PY - 2014/03/25/revised PY - 2014/03/28/accepted PY - 2014/5/3/entrez PY - 2014/5/3/pubmed PY - 2015/2/13/medline KW - Electron transport KW - Entorhinal cortex KW - Hippocampus KW - Microarray KW - Mitochondria KW - Neurotransmitter receptor KW - SNARE KW - Somatosensory cortex KW - Superior frontal gyrus KW - Synapse SP - 1961 EP - 72 JF - Neurobiology of aging JO - Neurobiol Aging VL - 35 IS - 9 N2 - Mild cognitive impairment (MCI) represents a cognitive state intermediate between normal aging and early Alzheimer's disease (AD). To investigate if the molecular signature of MCI parallels the clinical picture, we use microarrays to extensively profile gene expression in 4 cortical brain regions (entorhinal cortex, hippocampus, superior frontal gyrus, post-central gyrus) using the postmortem tissue from cognitively normal aged controls, MCI, and AD cases. Our data reveal that gene expression patterns in MCI are not an extension of aging, and for the most part, are not intermediate between aged controls and AD. Functional enrichment analysis of significant genes revealed prominent upregulation in MCI brains of genes associated with anabolic and biosynthetic pathways (notably transcription, protein biosynthesis, protein trafficking, and turnover) as well as mitochondrial energy generation. In addition, many synaptic genes showed altered expression in MCI, predominantly upregulation, including genes for central components of the vesicle fusion machinery at the synapse, synaptic vesicle trafficking, neurotransmitter receptors, and synaptic structure and stabilization. These data suggest that there is a rebalancing of synaptic transmission in the MCI brain. To investigate if synaptic gene expression levels in MCI were related to cognitive function, Pearson correlation coefficient between the Mini Mental State Examination (MMSE) and region-specific messenger RNA expression were computed for MCI cases. A number of synaptic genes showed strong significant correlations (r > 0.8, p < 0.01) most notably in the entorhinal cortex, with fewer in the hippocampus, and very few in neocortical regions. The synaptic genes with highly significant correlations were predominantly related to synaptic transmission and plasticity, and myelin composition. Unexpectedly, we found that gene expression changes that facilitate synaptic excitability and plasticity were overwhelmingly associated with poorer MMSE, and conversely that gene expression changes that inhibit plasticity were positively associated with MMSE. These data suggest that there are excessive excitability and apparent plasticity in limbic brain regions in MCI, that is associated with impaired synaptic and cognitive function. Such changes would be predicted to contribute to increased excitability, in turn leading to greater metabolic demand and ultimately progressive degeneration and AD, if not controlled. SN - 1558-1497 UR - https://www.unboundmedicine.com/medline/citation/24786631/Brain_gene_expression_patterns_differentiate_mild_cognitive_impairment_from_normal_aged_and_Alzheimer's_disease_ DB - PRIME DP - Unbound Medicine ER -