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1.
Nature ; 556(7701): 332-338, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29643512

RESUMO

Innate immune memory is a vital mechanism of myeloid cell plasticity that occurs in response to environmental stimuli and alters subsequent immune responses. Two types of immunological imprinting can be distinguished-training and tolerance. These are epigenetically mediated and enhance or suppress subsequent inflammation, respectively. Whether immune memory occurs in tissue-resident macrophages in vivo and how it may affect pathology remains largely unknown. Here we demonstrate that peripherally applied inflammatory stimuli induce acute immune training and tolerance in the brain and lead to differential epigenetic reprogramming of brain-resident macrophages (microglia) that persists for at least six months. Strikingly, in a mouse model of Alzheimer's pathology, immune training exacerbates cerebral ß-amyloidosis and immune tolerance alleviates it; similarly, peripheral immune stimulation modifies pathological features after stroke. Our results identify immune memory in the brain as an important modifier of neuropathology.


Assuntos
Encéfalo/imunologia , Encéfalo/patologia , Imunidade Inata , Memória Imunológica , Doenças do Sistema Nervoso/imunologia , Doenças do Sistema Nervoso/patologia , Doença de Alzheimer/imunologia , Doença de Alzheimer/patologia , Amiloidose/imunologia , Amiloidose/patologia , Animais , Modelos Animais de Doenças , Epigênese Genética , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Tolerância Imunológica , Inflamação/genética , Inflamação/imunologia , Masculino , Camundongos , Microglia/imunologia , Microglia/metabolismo , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/patologia
2.
Proc Natl Acad Sci U S A ; 116(39): 19727-19735, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31492812

RESUMO

Prion diseases are fatal neurodegenerative disorders caused by misfolding of the normal prion protein into an infectious cellular pathogen. Clinically characterized by rapidly progressive dementia and accounting for 85% of human prion disease cases, sporadic Creutzfeldt-Jakob disease (sCJD) is the prevalent human prion disease. Although sCJD neuropathological hallmarks are well-known, associated molecular alterations are elusive due to rapid progression and absence of preclinical stages. To investigate transcriptome alterations during disease progression, we utilized tg340-PRNP129MM mice infected with postmortem material from sCJD patients of the most susceptible genotype (MM1 subtype), a sCJD model that faithfully recapitulates the molecular and pathological alterations of the human disease. Here we report that transcriptomic analyses from brain cortex in the context of disease progression, reveal epitranscriptomic alterations (specifically altered RNA edited pathway profiles, eg., ER stress, lysosome) that are characteristic and possibly protective mainly for preclinical and clinical disease stages. Our results implicate regulatory epitranscriptomic mechanisms in prion disease neuropathogenesis, whereby RNA-editing targets in a humanized sCJD mouse model were confirmed in pathological human autopsy material.


Assuntos
Doenças Priônicas/genética , Doenças Priônicas/metabolismo , Edição de RNA/genética , Animais , Encéfalo/metabolismo , Síndrome de Creutzfeldt-Jakob/genética , Modelos Animais de Doenças , Progressão da Doença , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Genótipo , Humanos , Camundongos , Proteínas Priônicas/genética , Príons/metabolismo , Edição de RNA/fisiologia , Transcriptoma/genética
3.
RNA Biol ; 17(1): 112-124, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31538530

RESUMO

The duck represents an important reservoir of influenza viruses for transmission to other avian and mammalian hosts, including humans. The increased pathogenicity of the recently emerging clades of highly pathogenic avian influenza (HPAI) viruses of the H5N1 subtype in ducks features systemic viral spread and organ-to-organ variation in viral transcription and tissue damage. We previously reported that experimental infection of Sudani ducks (Cairina moschata) with an Egyptian HPAI (H5N1) virus (clade 2.2.1.2) features high viral replication and severe tissue damage in lung, but lower viral replication and only mild histological changes in brain. Little is known about the involvement of miRNA in organ-specific responses to H5N1 viruses in ducks, and involvement of the other classes of small noncoding RNA (sncRNA) has not been investigated so far. Following RNA sequencing, we have annotated the duck sncRNome and compared global expression changes of the four major sncRNA classes (miRNAs, piRNAs, snoRNAs, snRNAs) between duck lung and brain during a 120 h time course of infection with this HPAI strain. We find major organ-specific differences in miRNA, piRNA and snoRNA populations even before infection and substantial reprogramming of all sncRNA classes throughout infection, which was less pronounced in brain. Pathway prediction analysis of miRNA targets revealed enrichment of inflammation-, infection- and apoptosis-related pathways in lung, but enrichment of metabolism-related pathways (including tryptophan metabolism) in brain. Thus, organ-specific differences in sncRNA responses may contribute to differences in viral replication and organ damage in ducks infected with isolates from this emerging HPAI clade, and likely other strains.


Assuntos
Patos/genética , Patos/virologia , Interações Hospedeiro-Patógeno/genética , Virus da Influenza A Subtipo H5N1/fisiologia , Influenza Aviária/genética , Influenza Aviária/virologia , Pequeno RNA não Traduzido/genética , Animais , Mapeamento Cromossômico , Perfilação da Expressão Gênica , Virus da Influenza A Subtipo H5N1/patogenicidade , Influenza Aviária/metabolismo , MicroRNAs/genética , Especificidade de Órgãos/genética
4.
BMC Bioinformatics ; 19(1): 54, 2018 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-29444641

RESUMO

BACKGROUND: Small RNA molecules play important roles in many biological processes and their dysregulation or dysfunction can cause disease. The current method of choice for genome-wide sRNA expression profiling is deep sequencing. RESULTS: Here we present Oasis 2, which is a new main release of the Oasis web application for the detection, differential expression, and classification of small RNAs in deep sequencing data. Compared to its predecessor Oasis, Oasis 2 features a novel and speed-optimized sRNA detection module that supports the identification of small RNAs in any organism with higher accuracy. Next to the improved detection of small RNAs in a target organism, the software now also recognizes potential cross-species miRNAs and viral and bacterial sRNAs in infected samples. In addition, novel miRNAs can now be queried and visualized interactively, providing essential information for over 700 high-quality miRNA predictions across 14 organisms. Robust biomarker signatures can now be obtained using the novel enhanced classification module. CONCLUSIONS: Oasis 2 enables biologists and medical researchers to rapidly analyze and query small RNA deep sequencing data with improved precision, recall, and speed, in an interactive and user-friendly environment. AVAILABILITY AND IMPLEMENTATION: Oasis 2 is implemented in Java, J2EE, mysql, Python, R, PHP and JavaScript. It is freely available at https://oasis.dzne.de.


Assuntos
Pequeno RNA não Traduzido/genética , Análise de Sequência de RNA/métodos , Estatística como Assunto/métodos , Sequência de Bases , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , MicroRNAs/genética , Software
5.
Neurobiol Dis ; 119: 121-135, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30092270

RESUMO

Alpha-synuclein (aSyn) is the major protein component of Lewy bodies and Lewy neurites, the typical pathological hallmarks in Parkinson's disease (PD) and Dementia with Lewy bodies. aSyn is capable of inducing transcriptional deregulation, but the precise effect of specific aSyn mutants associated with familial forms of PD, remains unclear. Here, we used transgenic mice overexpressing human wild-type (WT) or A30P aSyn to compare the transcriptional profiles of the two animal models. We found that A30P aSyn promotes strong transcriptional deregulation and increases DNA binding. Interestingly, COL4A2, a major component of basement membranes, was found to be upregulated in both A30P aSyn transgenic mice and in dopaminergic neurons expressing A30P aSyn, suggesting a crucial role for collagen related genes in aSyn-induced toxicity. Finally, we observed that A30P aSyn alters Golgi morphology and increases the susceptibility to endoplasmic reticulum (ER) stress in dopaminergic cells. In total, our findings provide novel insight into the putative role of aSyn on transcription and on the molecular mechanisms involved, thereby opening novel avenues for future therapeutic interventions in PD and other synucleinopathies.


Assuntos
Colágeno Tipo IV/biossíntese , Retículo Endoplasmático/fisiologia , Complexo de Golgi/fisiologia , Fragmentos de Peptídeos/biossíntese , alfa-Sinucleína/biossíntese , Animais , Células Cultivadas , Colágeno Tipo IV/genética , Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fragmentos de Peptídeos/genética , alfa-Sinucleína/genética
6.
EMBO J ; 33(17): 1912-27, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-25024434

RESUMO

Neuronal histone acetylation has been linked to memory consolidation, and targeting histone acetylation has emerged as a promising therapeutic strategy for neuropsychiatric diseases. However, the role of histone-modifying enzymes in the adult brain is still far from being understood. Here we use RNA sequencing to screen the levels of all known histone acetyltransferases (HATs) in the hippocampal CA1 region and find that K-acetyltransferase 2a (Kat2a)--a HAT that has not been studied for its role in memory function so far--shows highest expression. Mice that lack Kat2a show impaired hippocampal synaptic plasticity and long-term memory consolidation. We furthermore show that Kat2a regulates a highly interconnected hippocampal gene expression network linked to neuroactive receptor signaling via a mechanism that involves nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). In conclusion, our data establish Kat2a as a novel and essential regulator of hippocampal memory consolidation.


Assuntos
Regulação da Expressão Gênica , Redes Reguladoras de Genes , Histona Acetiltransferases/metabolismo , Memória , Animais , Região CA1 Hipocampal/enzimologia , Perfilação da Expressão Gênica , Histona Acetiltransferases/genética , Camundongos , Camundongos Knockout
7.
Bioinformatics ; 31(13): 2205-7, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-25701573

RESUMO

UNLABELLED: Oasis is a web application that allows for the fast and flexible online analysis of small-RNA-seq (sRNA-seq) data. It was designed for the end user in the lab, providing an easy-to-use web frontend including video tutorials, demo data and best practice step-by-step guidelines on how to analyze sRNA-seq data. Oasis' exclusive selling points are a differential expression module that allows for the multivariate analysis of samples, a classification module for robust biomarker detection and an advanced programming interface that supports the batch submission of jobs. Both modules include the analysis of novel miRNAs, miRNA targets and functional analyses including GO and pathway enrichment. Oasis generates downloadable interactive web reports for easy visualization, exploration and analysis of data on a local system. Finally, Oasis' modular workflow enables for the rapid (re-) analysis of data. AVAILABILITY AND IMPLEMENTATION: Oasis is implemented in Python, R, Java, PHP, C++ and JavaScript. It is freely available at http://oasis.dzne.de. CONTACT: stefan.bonn@dzne.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Biologia Computacional/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , MicroRNAs/análise , Sistemas On-Line , Análise de Sequência de RNA/métodos , Software , Humanos , Internet , MicroRNAs/genética
8.
Sci Transl Med ; 15(680): eabn7979, 2023 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-36346321

RESUMO

Genome sequences from evolving infectious pathogens allow quantification of case introductions and local transmission dynamics. We sequenced 11,357 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes from Switzerland in 2020-the sixth largest effort globally. Using a representative subset of these data, we estimated viral introductions to Switzerland and their persistence over the course of 2020. We contrasted these estimates with simple null models representing the absence of certain public health measures. We show that Switzerland's border closures decoupled case introductions from incidence in neighboring countries. Under a simple model, we estimate an 86 to 98% reduction in introductions during Switzerland's strictest border closures. Furthermore, the Swiss 2020 partial lockdown roughly halved the time for sampled introductions to die out. Last, we quantified local transmission dynamics once introductions into Switzerland occurred using a phylodynamic model. We found that transmission slowed 35 to 63% upon outbreak detection in summer 2020 but not in fall. This finding may indicate successful contact tracing over summer before overburdening in fall. The study highlights the added value of genome sequencing data for understanding transmission dynamics.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , COVID-19/genética , Saúde Pública , Suíça/epidemiologia , Controle de Doenças Transmissíveis , Genoma Viral/genética , Filogenia
9.
Sci Adv ; 7(38): eabc6792, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34524839

RESUMO

Increase in the size of human neocortex­acquired in evolution­accounts for the unique cognitive capacity of humans. This expansion reflects the evolutionarily enhanced proliferative ability of basal progenitors (BPs), including the basal radial glia and basal intermediate progenitors (bIPs) in mammalian cortex, which may have been acquired through epigenetic alterations in BPs. However, how the epigenome in BPs differs across species is not known. Here, we report that histone H3 acetylation is a key epigenetic regulation in bIP amplification and cortical expansion. Through epigenetic profiling of sorted bIPs, we show that histone H3 lysine 9 acetylation (H3K9ac) is low in murine bIPs and high in human bIPs. Elevated H3K9ac preferentially increases bIP proliferation, increasing the size and folding of the normally smooth mouse neocortex. H3K9ac drives bIP amplification by increasing expression of the evolutionarily regulated gene, Trnp1, in developing cortex. Our findings demonstrate a previously unknown mechanism that controls cortical architecture.

10.
Eur J Heart Fail ; 22(1): 54-66, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31849158

RESUMO

AIMS: Deregulation of epigenetic processes and aberrant gene expression are important mechanisms in heart failure. Here we studied the potential relevance of m6A RNA methylation in heart failure development. METHODS AND RESULTS: We analysed m6A RNA methylation via next-generation sequencing. We found that approximately one quarter of the transcripts in the healthy mouse and human heart exhibit m6A RNA methylation. During progression to heart failure we observed that changes in m6A RNA methylation exceed changes in gene expression both in mouse and human. RNAs with altered m6A RNA methylation were mainly linked to metabolic and regulatory pathways, while changes in RNA expression level mainly represented changes in structural plasticity. Mechanistically, we could link m6A RNA methylation to altered RNA translation and protein production. Interestingly, differentially methylated but not differentially expressed RNAs showed differential polysomal occupancy, indicating transcription-independent modulation of translation. Furthermore, mice with a cardiomyocyte restricted knockout of the RNA demethylase Fto exhibited an impaired cardiac function compared to control mice. CONCLUSIONS: We could show that m6A landscape is altered in heart hypertrophy and heart failure. m6A RNA methylation changes lead to changes in protein abundance, unconnected to mRNA levels. This uncovers a new transcription-independent mechanisms of translation regulation. Therefore, our data suggest that modulation of epitranscriptomic processes such as m6A methylation might be an interesting target for therapeutic interventions.


Assuntos
Insuficiência Cardíaca , Animais , Epigênese Genética , Insuficiência Cardíaca/genética , Metilação , Camundongos , RNA/genética , RNA/metabolismo , RNA Mensageiro/genética
11.
Cell Rep ; 23(2): 546-554, 2018 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-29642011

RESUMO

Physical exercise in combination with cognitive training is known to enhance synaptic plasticity, learning, and memory and lower the risk for various complex diseases including Alzheimer's disease. Here, we show that exposure of adult male mice to an environmental enrichment paradigm leads to enhancement of synaptic plasticity and cognition also in the next generation. We show that this effect is mediated through sperm RNA and especially miRs 212/132. In conclusion, our study reports intergenerational inheritance of an acquired cognitive benefit and points to specific miRs as candidates mechanistically involved in this type of transmission.


Assuntos
Plasticidade Neuronal/fisiologia , Condicionamento Físico Animal , RNA/metabolismo , Animais , Comportamento Animal , Encéfalo/metabolismo , Cognição/fisiologia , Potenciais Pós-Sinápticos Excitadores , Hipocampo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/química , MicroRNAs/metabolismo , RNA/química , RNA/isolamento & purificação , Análise de Sequência de RNA , Meio Social , Espermatozoides/metabolismo
12.
Cell Rep ; 20(3): 538-548, 2017 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-28723559

RESUMO

Kmt2a and Kmt2b are H3K4 methyltransferases of the Set1/Trithorax class. We have recently shown the importance of Kmt2b for learning and memory. Here, we report that Kmt2a is also important in memory formation. We compare the decrease in H3K4 methylation and de-regulation of gene expression in hippocampal neurons of mice with knockdown of either Kmt2a or Kmt2b. Kmt2a and Kmt2b control largely distinct genomic regions and different molecular pathways linked to neuronal plasticity. Finally, we show that the decrease in H3K4 methylation resulting from Kmt2a knockdown partially recapitulates the pattern previously reported in CK-p25 mice, a model for neurodegeneration and memory impairment. Our findings point to the distinct functions of even closely related histone-modifying enzymes and provide essential insight for the development of more efficient and specific epigenetic therapies against brain diseases.


Assuntos
Regulação Enzimológica da Expressão Gênica , Hipocampo/enzimologia , Histona-Lisina N-Metiltransferase/biossíntese , Memória , Proteína de Leucina Linfoide-Mieloide/biossíntese , Neurônios/enzimologia , Animais , Histona-Lisina N-Metiltransferase/genética , Metilação , Camundongos , Proteína de Leucina Linfoide-Mieloide/genética
13.
Cell Rep ; 17(4): 1071-1086, 2016 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-27720640

RESUMO

Endophilin-A, a well-characterized endocytic adaptor essential for synaptic vesicle recycling, has recently been linked to neurodegeneration. We report here that endophilin-A deficiency results in impaired movement, age-dependent ataxia, and neurodegeneration in mice. Transcriptional analysis of endophilin-A mutant mice, complemented by proteomics, highlighted ataxia- and protein-homeostasis-related genes and revealed upregulation of the E3-ubiquitin ligase FBXO32/atrogin-1 and its transcription factor FOXO3A. FBXO32 overexpression triggers apoptosis in cultured cells and neurons but, remarkably, coexpression of endophilin-A rescues it. FBXO32 interacts with all three endophilin-A proteins. Similarly to endophilin-A, FBXO32 tubulates membranes and localizes on clathrin-coated structures. Additionally, FBXO32 and endophilin-A are necessary for autophagosome formation, and both colocalize transiently with autophagosomes. Our results point to a role for endophilin-A proteins in autophagy and protein degradation, processes that are impaired in their absence, potentially contributing to neurodegeneration and ataxia.


Assuntos
Aciltransferases/deficiência , Autofagia , Encéfalo/metabolismo , Proteína Forkhead Box O3/metabolismo , Proteínas Musculares/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Ligases SKP Culina F-Box/metabolismo , Ubiquitina/metabolismo , Aciltransferases/metabolismo , Envelhecimento/patologia , Animais , Apoptose , Ataxia/genética , Ataxia/patologia , Autofagossomos/metabolismo , Proteína Forkhead Box O3/genética , Células HeLa , Hipocampo/metabolismo , Hipocampo/patologia , Homeostase/genética , Humanos , Masculino , Camundongos , Camundongos Knockout , Transtornos dos Movimentos/complicações , Transtornos dos Movimentos/patologia , Proteínas Musculares/genética , Mutação/genética , Degeneração Neural/complicações , Degeneração Neural/patologia , Doença de Parkinson/genética , Doença de Parkinson/patologia , Ligação Proteica , Proteínas Ligases SKP Culina F-Box/genética , Transcrição Gênica , Regulação para Cima
14.
Nat Neurosci ; 19(1): 102-10, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26656643

RESUMO

The ability to form memories is a prerequisite for an organism's behavioral adaptation to environmental changes. At the molecular level, the acquisition and maintenance of memory requires changes in chromatin modifications. In an effort to unravel the epigenetic network underlying both short- and long-term memory, we examined chromatin modification changes in two distinct mouse brain regions, two cell types and three time points before and after contextual learning. We found that histone modifications predominantly changed during memory acquisition and correlated surprisingly little with changes in gene expression. Although long-lasting changes were almost exclusive to neurons, learning-related histone modification and DNA methylation changes also occurred in non-neuronal cell types, suggesting a functional role for non-neuronal cells in epigenetic learning. Finally, our data provide evidence for a molecular framework of memory acquisition and maintenance, wherein DNA methylation could alter the expression and splicing of genes involved in functional plasticity and synaptic wiring.


Assuntos
Comportamento Animal/fisiologia , Região CA1 Hipocampal/metabolismo , Cromatina/química , Metilação de DNA/fisiologia , Epigênese Genética/fisiologia , Expressão Gênica/fisiologia , Giro do Cíngulo/metabolismo , Histonas/metabolismo , Memória de Longo Prazo/fisiologia , Memória de Curto Prazo/fisiologia , Plasticidade Neuronal/fisiologia , Animais , Condicionamento Psicológico , Metilação de DNA/genética , Epigênese Genética/genética , Medo , Expressão Gênica/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/genética
15.
J Clin Invest ; 125(9): 3572-84, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26280576

RESUMO

Aging and increased amyloid burden are major risk factors for cognitive diseases such as Alzheimer's disease (AD). Effective therapies for these diseases are lacking. Here, we evaluated mouse models of age-associated memory impairment and amyloid deposition to study transcriptome and cell type-specific epigenome plasticity in the brain and peripheral organs. We determined that aging and amyloid pathology are associated with inflammation and impaired synaptic function in the hippocampal CA1 region as the result of epigenetic-dependent alterations in gene expression. In both amyloid and aging models, inflammation was associated with increased gene expression linked to a subset of transcription factors, while plasticity gene deregulation was differentially mediated. Amyloid pathology impaired histone acetylation and decreased expression of plasticity genes, while aging altered H4K12 acetylation-linked differential splicing at the intron-exon junction in neurons, but not nonneuronal cells. Furthermore, oral administration of the clinically approved histone deacetylase inhibitor vorinostat not only restored spatial memory, but also exerted antiinflammatory action and reinstated epigenetic balance and transcriptional homeostasis at the level of gene expression and exon usage. This study provides a systems-level investigation of transcriptome plasticity in the hippocampal CA1 region in aging and AD models and suggests that histone deacetylase inhibitors should be further explored as a cost-effective therapeutic strategy against age-associated cognitive decline.


Assuntos
Doença de Alzheimer , Região CA1 Hipocampal , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Memória/efeitos dos fármacos , Transcriptoma , Acetilação/efeitos dos fármacos , Envelhecimento , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Amiloide/genética , Amiloide/metabolismo , Animais , Região CA1 Hipocampal/enzimologia , Região CA1 Hipocampal/patologia , Modelos Animais de Doenças , Histonas/genética , Histonas/metabolismo , Humanos , Camundongos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética , Vorinostat
16.
Front Cell Neurosci ; 8: 373, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25431548

RESUMO

Aging is accompanied by gradually increasing impairment of cognitive abilities and constitutes the main risk factor of neurodegenerative conditions like Alzheimer's disease (AD). The underlying mechanisms are however not well understood. Here we analyze the hippocampal transcriptome of young adult mice and two groups of mice at advanced age using RNA sequencing. This approach enabled us to test differential expression of coding and non-coding transcripts, as well as differential splicing and RNA editing. We report a specific age-associated gene expression signature that is associated with major genetic risk factors for late-onset AD (LOAD). This signature is dominated by neuroinflammatory processes, specifically activation of the complement system at the level of increased gene expression, while de-regulation of neuronal plasticity appears to be mediated by compromised RNA splicing.

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