Polyadenylated Messenger RNA in Paired Helical Filament-Immunoreactive Neurons in Alzheimer Disease

Griffin, W. Sue T.; Chen, Ling; White, Charles L.; Morrison‐Bogorad, Marcelle

doi:10.1097/00002093-199040200-00001

Cited by 18 publications

(7 citation statements)

References 34 publications

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“…Total hybridization signal intensity (normalized to CREB mRNA) was downregulated in single AD NFT-bearing neurons compared with normal CA1 neurons by approximately 28% and 36% on the GDA and custom cDNA arrays, respectively, and this is consistent with previous semiquantitative studies of polyA ϩ mRNA expression in AD. [25][26][27][28] A summary of the relative changes for greater than 75 mRNAs is presented in Figure 4D. As a class, mRNAs for protein phosphatase subunits (␣ and ␤ subunits of PP1, A␣ and C␣ subunits of PP2A) displayed significant downregulation in CA1 neurons with NFTs compared with those without NFTs, which is consistent with the findings of other studies implicating reduced protein phosphatase activity in mechanisms of PHF formation.…”

Section: ) For Quantitative Comparisons Across Blots and Conditions supporting

confidence: 85%

Expression profile of transcripts in Alzheimer's disease tangle-bearing CA1 neurons

et al. 2000

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The pathogenesis of neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) is poorly understood, but changes in the expression of specific messenger RNAs (mRNAs) may reflect mechanisms underlying the formation of NFTs and their consequences in affected neurons. For these reasons, we compared the relative abundance of multiple mRNAs in tangle‐bearing versus normal CA1 neurons aspirated from sections of AD and control brains. Amplified antisense RNA expression profiling was performed on individual isolated neurons for analysis of greater than 18,000 expressed sequence tagged complementary DNAs (cDNAs) with cDNA microarrays, and further quantitative analyses were performed by reverse Northern blot analysis on 120 selected mRNAs on custom cDNA arrays. Relative to normal CA1 neurons, those harboring NFTs in AD brains showed significant reductions in several classes of mRNAs that are known to encode proteins implicated in AD neuropathology, including phosphatases/kinases, cytoskeletal proteins, synaptic proteins, glutamate receptors, and dopamine receptors. Because cathepsin D mRNA was upregulated in NFT‐bearing CA1 neurons in AD brains, we performed immunohistochemical studies that demonstrated abundant cathepsin D immunoreactivity in the same population of tangle‐bearing CA1 neurons. In addition, levels of mRNAs encoding proteins not previously implicated in AD were reduced in CA1 tangle‐bearing neurons, suggesting that these proteins (eg, activity‐regulated cytoskeleton‐associated protein, focal adhesion kinase, glutaredoxin, utrophin) may be novel mediators of NFT formation or degeneration in affected neurons. Thus, the profile of mRNAs differentially expressed by tangle‐bearing CA1 neurons may represent a “molecular fingerprint” of these neurons, and we speculate that mRNA expression profiles of diseased neurons in AD may suggest new directions for AD research or identify novel targets for developing more effective AD therapies. Ann Neurol 2000;48:77–87

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Section: ) For Quantitative Comparisons Across Blots and Conditions supporting

confidence: 85%

Expression profile of transcripts in Alzheimer's disease tangle-bearing CA1 neurons

et al. 2000

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“…1A. Total hybridization signal intensity is down-regulated in single AD NFT-bearing neurons compared to normal CA1 neurons by approximately 28%-36%, consistent with previous semiquantitative studies of polyadenylated mRNA expression in AD (58,59). Amyloid-␤ protein precursor (APP) mRNA is decreased approximately twofold on both high-density and custom-designed cDNA arrays, potentially indicating that NFT-bearing neurons express less APP mRNA in affected regions of the AD brain.…”

Section: Single-cell Analysis In Ad: Neurofibrillary Tanglessupporting

confidence: 85%

Single-Cell Gene Expression Analysis: Implications for Neurodegenerative and Neuropsychiatric Disorders

et al. 2004

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Technical and experimental advances in microaspiration techniques, RNA amplification, quantitative real-time polymerase chain reaction (qPCR), and cDNA microarray analysis have led to an increase in the number of studies of single-cell gene expression. In particular, the central nervous system (CNS) is an ideal structure to apply single-cell gene expression paradigms. Unlike an organ that is composed of one principal cell type, the brain contains a constellation of neuronal and noneuronal populations of cells. A goal is to sample gene expression from similar cell types within a defined region without potential contamination by expression profiles of adjacent neuronal subpopulations and noneuronal cells. The unprecedented resolution afforded by singlecell RNA analysis in combination with cDNA microarrays and qPCR-based analyses allows for relative gene expression level comparisons across cell types under different experimental conditions and disease states. The ability to analyze single cells is an important distinction from global and regional assessments of mRNA expression and can be applied to optimally prepared tissues from animal models as well as postmortem human brain tissues. This focused review illustrates the potential power of single-cell gene expression studies within the CNS in relation to neurodegenerative and neuropsychiatric disorders such as Alzheimer's disease (AD) and schizophrenia, respectively. KEY WORDS:Alzheimer's disease; cDNA microarray; cholinergic basal forebrain; dopamine receptors; expression profiling; protein phosphatases; RNA amplification; schizophrenia; single-cell microaspiration. Abbreviations (note the use of the NCBI-Unigene annotation): 3Rtau, three-repeat tau; 4Rtau, four-repeat tau; ACT, alpha-1-antichymotrypsin; ACTB, beta-actin; AGER, advanced glycosylation end product-specific receptor; APOE, apolipoprotein E; APP, amyloid-beta precursor protein; arc, activity regulated cytoskeletal-associated protein; BAX,

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“…Barton and Hardy, 1987;Perrett et al, 1988) or cell type in which they are expressed (Kobayashi et al, 1990). A further indication that extensive but incomplete degradation is unlikely to be occurring is the failure to see a consistent decline in poly(A)+ mRNA content with PMI, as determined by hybridization to poly(A) tails of mRNA (Tables 1 and 2; see also Griffin et al, 1990). Because removal of the poly(A) tail and degradation from the 3' end is the primary pathway of mRNA breakdown (Bernstein and Ross, 1989;Brawerman, 1990), it would be predicted that poly(A) tail detection would be particularly susceptible to PMI if pronounced partial degradation were occurring.…”

Section: Pmi and The Intactness Of Rnamentioning

confidence: 99%

Pre‐and Postmortem Influences on Brain RNA

Barton

Pearson

Najlerahim

et al. 1993

Journal of Neurochemistry

243

142

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Many potentially valuable techniques for the understanding of human neurobiological and neuropathological processes require the use of RNA obtained from postmortem tissue. As with earlier neurochemical studies, there are two particular problems posed by such tissue in comparison with tissue from experimental animals. These are the postmortem interval and the condition of the patient prior to death, referred to as the agonal state. We review the nature and extent of the effects of postmortem interval and agonal state on RNA in brain tissue, with particular reference to the study of neuropsychiatric disorders. Perhaps surprisingly, postmortem interval has at most a modest effect on RNA. Abundant intact and biologically active RNA is present in tissue frozen 36 h or more after death. Postmortem interval does not account for the marked variability observed among human brains in all RNA parameters. Despite the overall stability of RNA after death, some evidence suggests that individual RNAs may undergo postmortem decay. Less attention has been paid to the effects of agonal state. The existing data indicate that events in the premortem period such as hypoxia and coma can affect the amount of some messenger RNAs. The nature of agonal state influences depends on the messenger RNA in question, though the basis for this selective vulnerability is unknown. No agonal state effect on overall RNA level or activity has been found. The data show that postmortem brain tissue can be used for RNA research. However, considerable attention must be paid to controlling for the influences of pre-and postmortem factors, especially when quantitative analyses are performed.

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Polyadenylated Messenger RNA in Paired Helical Filament-Immunoreactive Neurons in Alzheimer Disease

Cited by 18 publications

References 34 publications

Expression profile of transcripts in Alzheimer's disease tangle-bearing CA1 neurons

Expression profile of transcripts in Alzheimer's disease tangle-bearing CA1 neurons

Single-Cell Gene Expression Analysis: Implications for Neurodegenerative and Neuropsychiatric Disorders

Pre‐and Postmortem Influences on Brain RNA

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