Gene expression correlates of neurofibrillary tangles in Alzheimer's disease

Dunckley, Travis; Beach, Thomas G.; Ramsey, Keri; Grover, Andrew; Mastroeni, Diego; Walker, Douglas G.; LaFleur, Bonnie; Coon, Keith D.; Brown, Kevin M.; Caselli, Richard J.; Kukull, Walter A.; Higdon, Roger; McKeel, Daniel W.; Morris, John C.; Hulette, Christine M.; Schmechel, Donald E.; Reiman, Eric M.; Rogers, Joseph; Stephan, Dietrich A.

doi:10.1016/j.neurobiolaging.2005.08.013

Cited by 156 publications

(138 citation statements)

References 33 publications

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“…We evaluated laser capture‐microdissected cortical neurons containing NFTs from AD brains (GEO accession GDS2795) and compared them to adjacent histopathologically normal neurons for a within‐subject study design (Dunckley et al, 2006). NFT‐containing neurons upregulated genes involved in cell survival and viability, inflammation, cell cycle progression and molecular transport and downregulated apoptosis, necrosis, and cell death pathways (Figure 1a).…”

Section: Resultsmentioning

confidence: 99%

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Tau protein aggregation is associated with cellular senescence in the brain

et al. 2018

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Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), traumatic brain injury (TBI), and over twenty others. Tau‐containing neurofibrillary tangle (NFT) accumulation is the closest correlate with cognitive decline and cell loss (Arriagada, Growdon, Hedley‐Whyte, & Hyman, 1992), yet mechanisms mediating tau toxicity are poorly understood. NFT formation does not induce apoptosis (de Calignon, Spires‐Jones, Pitstick, Carlson, & Hyman, 2009), which suggests that secondary mechanisms are driving toxicity. Transcriptomic analyses of NFT‐containing neurons microdissected from postmortem AD brain revealed an expression profile consistent with cellular senescence. This complex stress response induces aberrant cell cycle activity, adaptations to maintain survival, cellular remodeling, and metabolic dysfunction. Using four AD transgenic mouse models, we found that NFTs, but not Aβ plaques, display a senescence‐like phenotype. Cdkn2a transcript level, a hallmark measure of senescence, directly correlated with brain atrophy and NFT burden in mice. This relationship extended to postmortem brain tissue from humans with PSP to indicate a phenomenon common to tau toxicity. Tau transgenic mice with late‐stage pathology were treated with senolytics to remove senescent cells. Despite the advanced age and disease progression, MRI brain imaging and histopathological analyses indicated a reduction in total NFT density, neuron loss, and ventricular enlargement. Collectively, these findings indicate a strong association between the presence of NFTs and cellular senescence in the brain, which contributes to neurodegeneration. Given the prevalence of tau protein deposition among neurodegenerative diseases, these findings have broad implications for understanding, and potentially treating, dozens of brain diseases.

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Section: Resultsmentioning

confidence: 99%

“…The GEO accessions GDS2795 and GSE56772 were accessed from the GEO Profiles database (Barrett et al, 2013; Dunckley et al, 2006) with Rstudio version 1.0.143. Because the GDS2795 data set was a within‐subject design, ratios of NFT vs. CTL gene expression were generated for each subject.…”

Section: Methodsmentioning

confidence: 99%

Tau protein aggregation is associated with cellular senescence in the brain

et al. 2018

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“…Comparison of our study with two previously published gene profiling experiments [8,20] was used to identify genes that would reveal common pathophysiological mechanisms. First, differential gene expression related to cognitive decline was determined by combining transcripts differentially regulated in the comparisons of AD versus non-demented subjects in hippocampus [8], entorhinal cortex [20] and frontal cortex (this study).…”

Section: Identification Of Genes In Common Across Tissuesmentioning

confidence: 99%

“…First, differential gene expression related to cognitive decline was determined by combining transcripts differentially regulated in the comparisons of AD versus non-demented subjects in hippocampus [8], entorhinal cortex [20] and frontal cortex (this study). Because Blalock, et al [8] used the Affymetrix HG_U133A GeneChip array, we used a subset of data from the other two studies that corresponded to the Probe IDs found on the Affymetrix HG_U133A GeneChip.…”

Section: Identification Of Genes In Common Across Tissuesmentioning

confidence: 99%

“…Furthermore, since genes that are differentially expressed across tissues involved in AD pathology would provide valuable insight into common underlying genetic mechanisms in brain aging, we compared genes identified in this study, using frontal cortex, with genes identified in two other expression studies using hippocampus [8] and entorhinal cortex [20] . Genes that were differentially expressed across the three studies, emphasizing common themes of pathology underlying dementia, are key candidates for further studies of genetic risk factors for cognitive decline.…”

Section: Introductionmentioning

confidence: 99%

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Translational gene mapping of cognitive decline

Wilmot

McWeeney

Nixon

et al. 2008

Neurobiology of Aging

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The ability to maintain cognitive function during aging is a complex process subject to genetic and environmental influences. Alzheimer's disease (AD) is the most common disorder causing cognitive decline among the elderly. Among those with AD, there is broad variation in the relationship between AD neuropathology and clinical manifestations of dementia. Differences in expression of genes involved in neural processing pathways may contribute to individual differences in maintenance of cognitive function.We performed whole genome expression profiling of RNA obtained from frontal cortex of clinically non-demented and AD subjects to identify genes associated with brain aging and cognitive decline. Genetic mapping information and biological function annotation were incorporated to highlight genes of particular interest. The candidate genes identified in this study were compared with those from two other studies in different tissues to identify common underlying transcriptional profiles. In addition to confirming sweeping transcriptomal differences documented in previous studies of cognitive decline, we present new evidence for up-regulation of actin-related processes and downregulation of translation, RNA processing and localization, and vesicle-mediated transport in individuals with cognitive decline.

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Next generation transcriptomics and genomics elucidate biological complexity of microglia in health and disease

Wes

Holtman

Boddeke

et al. 2015

Glia

112

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Genome‐wide expression profiling technology has resulted in detailed transcriptome data for a wide range of tissues, conditions and diseases. In neuroscience, expression datasets were mostly generated using whole brain tissue samples, resulting in data from a mixture of cell types, including glial cells and neurons. Over the past few years, a rapidly increasing number of expression profiling studies using isolated microglial cell populations have been reported. In these studies, the microglia transcriptome was compared to other cell types, such as other brain cells and peripheral tissue macrophages, and related to aging and neurodegenerative conditions. A commonality found in many of these studies was that microglia possess distinct gene expression signatures. This repertoire of selectively‐expressed microglial genes highlight functions beyond immune responses, such as synaptic modulation and neurotrophic support, and open up avenues to explore as‐yet‐unexpected roles. These data provide improved understanding of disease pathology, and complement not only the aforementioned whole brain tissue transcriptome studies, but also genome‐ and epigenome‐wide association studies. In this review, insights obtained from isolated microglia transcriptome studies are presented, and compared to studies using other genome‐wide approaches. The relation of microglia to other tissue macrophages and glial cell populations, as well as the role of microglia in the aging brain and in neurodegenerative conditions, will be discussed. Many more of these types of studies are expected in the near future, hopefully leading to the identification of novel genes and targets for neurodegenerative conditions. GLIA 2016;64:197–213

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Gene expression correlates of neurofibrillary tangles in Alzheimer's disease

Cited by 156 publications

References 33 publications

Tau protein aggregation is associated with cellular senescence in the brain

Tau protein aggregation is associated with cellular senescence in the brain

Translational gene mapping of cognitive decline

Next generation transcriptomics and genomics elucidate biological complexity of microglia in health and disease

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