Transcriptional Alterations Related to Neuropathology and Clinical Manifestation of Alzheimer’s Disease

Silva, Aderbal R.T.; Grinberg, Lea T.; Farfel, José Marcelo; Diniz, Breno S.; Lima, Leandro A.; Silva, Paulo J. S.; Ferretti, Renata E.L.; Carraro, Dirce Maria; Brentani, Helena

doi:10.1371/journal.pone.0048751

Cited by 36 publications

(32 citation statements)

References 82 publications

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“…To assess differences in network organization between individuals with BD and SZ, co-expression of pairs of genes were evaluated as previously described (Silva et al, 2012). Briefly, the Pearson Correlation Coefficient (PCC) for each gene and partners in each group was calculated.…”

Section: Discussionmentioning

confidence: 99%

Innate immune response is differentially dysregulated between bipolar disease and schizophrenia

Baumont

Maschietto

Lima

et al. 2015

Schizophrenia Research

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Schizophrenia (SZ) and bipolar disorder (BD) are severe psychiatric conditions with a neurodevelopmental component. Genetic findings indicate the existence of an overlap in genetic susceptibility across the disorders. Also, image studies provide evidence for a shared neurobiological basis, contributing to a dimensional diagnostic approach. This study aimed to identify the molecular mechanisms that differentiate SZ and BD patients from health controls but also that distinguish both from health individuals. Comparison of gene expression profiling in post-mortem brains of both disorders and health controls (30 cases), followed by a further comparison between 29 BD and 29 SZ revealed 28 differentially expressed genes. These genes were used in co-expression analysesthat revealed the pairs CCR1/SERPINA1, CCR5/HCST, C1QA/CD68, CCR5/S100A11 and SERPINA1/TLR1 as presenting the most significant difference in co-expression between SZ and BD. Next, a protein-protein interaction (PPI) network using the 28 differentially expressed genes as seeds revealed CASP4, TYROBP, CCR1, SERPINA1, CCR5 and C1QA as having a central role in the diseases manifestation. Both co-expression and network topological analyses pointed to genes related to microglia functions. Based on this data, we suggest that differences between SZ and BP are due to genes involved with response to stimulus, defense response, immune system process and response to stress biological processes, all having a role in the communication of environmental factors to the cells and associated to microglia.

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Section: Discussionmentioning

confidence: 99%

Innate immune response is differentially dysregulated between bipolar disease and schizophrenia

Baumont

Maschietto

Lima

et al. 2015

Schizophrenia Research

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“…Specifically, the top four functional categories that predicted GMT decline (cellular proliferation, aggregation and differentiation, metabolism and the quantity of blood cells) are reported to regulate adult stem cell neurogenesis in mice (van Praag et al, 2005; Villeda et al, 2011). The same functional categories were also implicated in development of Alzheimer’s disease (Silva et al, 2011). This age-related downregulation of adult cellular proliferation pathways is a natural strategy to prevent unregulated cell growth.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomics of cortical gray matter thickness decline during normal aging

et al. 2013

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Introduction We performed a whole-transcriptome correlation analysis, followed by the pathway enrichment and testing of innate immune response pathways analyses to evaluate the hypothesis that transcriptional activity can predict cortical gray matter thickness (GMT) variability during normal cerebral aging Methods Transcriptome and GMT data were availabe for 379 individuals (age range=28–85) community-dwelling members of large extended Mexican-American families. Collection of transcriptome data preceded that of neuroimaging data by 17 years. Genome-wide gene transcriptome data consisted of 20,413 heritable lymphocytes-based transcripts. GMT measurements were performed from high-resolution (isotropic 800µm) T1-weighted MRI. Transcriptome-wide and pathway enrichment analysis was used to classify genes correlated with GMT. Transcripts for sixty genes from seven innate immune pathways were tested as specific predictors of GMT variability. Results Transcripts for eight genes (IGFBP3, LRRN3, CRIP2, SCD, IDS, TCF4, GATA3, HN1) passed the transcriptome-wide significance threshold. Four orthogonal factors extracted from this set predicted 31.9% of the variability in the whole-brain and between 23.4 and 35% of regional GMT measurements. Pathway enrichment analysis identified six functional categories including cellular proliferation, aggregation, differentiation, viral infection, and metabolism. The integrin signaling pathway was significantly (p<10−6) enriched with GMT. Finally, three innate immune pathways (complement signaling, toll-receptors and scavenger and immunoglobulins) were significantly associated with GMT. Conclusion Expression activity for the genes that regulate cellular proliferation, adhesion, differentiation and inflammation can explain a significant proportion of individual variability in cortical GMT. Our findings suggest that normal cerebral aging is the product of a progressive decline in regenerative capacity and increased neuroinflammation.

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“…To uncover the molecular aspects that underlie these pathophysiological processes and resilient brain aging, we performed a gene expression study among subjects with 1) clinical dementia and AD pathology (CP-AD), 2) AD pathology and healthy cognition (P-AD), and normal individuals (N) [24]. Genes involved in oxidative stress and in DNA damage/repair were found to be coupled with AD neuropathology.…”

Section: Introductionmentioning

confidence: 99%

Repair of Oxidative DNA Damage, Cell-Cycle Regulation and Neuronal Death May Influence the Clinical Manifestation of Alzheimer’s Disease

et al. 2014

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Alzheimer’s disease (AD) is characterized by progressive cognitive decline associated with a featured neuropathology (neuritic plaques and neurofibrillary tangles). Several studies have implicated oxidative damage to DNA, DNA repair, and altered cell-cycle regulation in addition to cell death in AD post-mitotic neurons. However, there is a lack of studies that systematically assess those biological processes in patients with AD neuropathology but with no evidence of cognitive impairment. We evaluated markers of oxidative DNA damage (8-OHdG, H2AX), DNA repair (p53, BRCA1, PTEN), and cell-cycle (Cdk1, Cdk4, Cdk5, Cyclin B1, Cyclin D1, p27Kip1, phospho-Rb and E2F1) through immunohistochemistry and cell death through TUNEL in autopsy hippocampal tissue samples arrayed in a tissue microarray (TMA) composed of three groups: I) “clinical-pathological AD” (CP-AD) - subjects with neuropathological AD (Braak≥IV and CERAD = B or C) and clinical dementia (CDR≥2, IQCODE>3.8); II) “pathological AD” (P-AD) - subjects with neuropathological AD (Braak≥IV and CERAD = B or C) and without cognitive impairment (CDR 0, IQCODE<3.2); and III) “normal aging” (N) - subjects without neuropathological AD (Braak≤II and CERAD 0 or A) and with normal cognitive function (CDR 0, IQCODE<3.2). Our results show that high levels of oxidative DNA damage are present in all groups. However, significant reductions in DNA repair and cell-cycle inhibition markers and increases in cell-cycle progression and cell death markers in subjects with CP-AD were detected when compared to both P-AD and N groups, whereas there were no significant differences in the studied markers between P-AD individuals and N subjects. This study indicates that, even in the setting of pathological AD, healthy cognition may be associated with a preserved repair to DNA damage, cell-cycle regulation, and cell death in post-mitotic neurons.

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Transcriptional Alterations Related to Neuropathology and Clinical Manifestation of Alzheimer’s Disease

Cited by 36 publications

References 82 publications

Innate immune response is differentially dysregulated between bipolar disease and schizophrenia

Innate immune response is differentially dysregulated between bipolar disease and schizophrenia

Transcriptomics of cortical gray matter thickness decline during normal aging

Repair of Oxidative DNA Damage, Cell-Cycle Regulation and Neuronal Death May Influence the Clinical Manifestation of Alzheimer’s Disease

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