Cited by 570Neuroinflammation and Neurodegeneration MechanismsGenetics, Aging, and Longevity in Model OrganismsNeurological Disease Mechanisms and Treatments

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Gene Microarrays in Hippocampal Aging: Statistical Profiling Identifies Novel Processes Correlated with Cognitive Impairment

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Blalock, Eric M., Chen, Kuey-Chu, Sharrow, Keith, Herman, James P., Porter, Nada M., Foster, Thomas C., Landfield, Philip W.·2003·The Journal of Neuroscience

DOI 10.1523/jneurosci.23-09-03807.2003PMC PMC6742177

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Abstract

Gene expression microarrays provide a powerful new tool for studying complex processes such as brain aging. However, inferences from microarray data are often hindered by multiple comparisons, small sample sizes, and uncertain relationships to functional endpoints. Here we sought gene expression correlates of aging-dependent cognitive decline, using statistical profiling of gene microarrays in well powered groups of young, mid-aged, and aged rats (n = 10 per group). Animals were trained on two memory tasks, and the hippocampal CA1 region of each was analyzed on an individual microarray (one chip per animal). Aging- and cognition-related genes were identified by testing each gene by ANOVA (for aging effects) and then by Pearson's test (correlating expression with memory). Genes identified by this algorithm were associated with several phenomena known to be aging-dependent, including inflammation, oxidative stress, altered protein processing, and decreased mitochondrial function, but also with multiple processes not previously linked to functional brain aging. These novel processes included downregulated early response signaling, biosynthesis and activity-regulated synaptogenesis, and upregulated myelin turnover, cholesterol synthesis, lipid and monoamine metabolism, iron utilization, structural reorganization, and intracellular Ca2+ release pathways. Multiple transcriptional regulators and cytokines also were identified. Although most gene expression changes began by mid-life, cognition was not clearly impaired until late life. Collectively, these results suggest a new integrative model of brain aging in which genomic alterations in early adulthood initiate interacting cascades of decreased signaling and synaptic plasticity in neurons, extracellular changes, and increased myelin turnover-fueled inflammation in glia that cumulatively induce aging-related cognitive impairment.

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Authors: Blalock, E. M., Chen, K.-C., Sharrow, K., Herman, J. P., Porter, N. M., Foster, T. C., & Landfield, P. W.
Affiliations: University of Kentucky (US)
University of Cincinnati (US)
ORCID: Blalock, Eric M.
Herman, James P.
Foster, Thomas C.
Venue: The Journal of Neuroscience
Publisher: Society for Neuroscience
Published: 2003-05-01
Volume: 23
Issue: 9
Pages: 3807-3819
ISSN: 0270-6474 (ISSN-L)
1529-2401
DOI: 10.1523/jneurosci.23-09-03807.2003
PMC: PMC6742177
OpenAlex: W2132977458
Cited by: 570
References: 85
Citations by year: 2026: 2 · 2025: 7 · 2024: 8 · 2023: 5 · 2022: 23 · 2021: 15 · 2020: 17 · 2019: 27 · 2018: 22 · 2017: 28 · 2016: 28 · 2015: 19 · 2014: 22 · 2013: 32 · 2012: 39
FWCI: 22.81
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Neuroscience (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5r01ag018228-02)
National Institute on Aging (P01AG010836, R01AG014979, AG 14979, AG 10836, AG18228, R37AG004542, AG 04542)
National Institute of Mental Health (MH 59891, R01MH059891)
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords: brain aging, hippocampal CA1, cognitive impairment, gene expression profiling, memory, inflammation, oxidative stress, mitochondrial function, myelin turnover, synaptogenesis, cholesterol biosynthesis, lipid metabolism, monoamine metabolism, iron utilization, intracellular calcium release, transcription factors, cytokines, synaptic plasticity, rats
MeSH terms: Aging, Algorithms, Animals, Behavior, Animal, Cognition, Cognition Disorders, Exploratory Behavior, Gene Expression Regulation, Hippocampus, Male, Memory, Psychomotor Performance, Rats, Inbred F344, Sensitivity and Specificity, Reproducibility of Results, DNA Probes, Biomarkers, Maze Learning, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Rats

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Gene Microarrays in Hippocampal Aging: Statistical Profiling Identifies Novel Processes Correlated with Cognitive Impairment

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