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BACKGROUND: Compromised autophagy, including impaired mitophagy and lysosomal function, plays pivotal roles in Alzheimer's disease (AD). Urolithin A (UA) is a gut microbial metabolite of ellagic acid that stimulates mitophagy. The effects of UA's long-term treatment of AD and mechanisms of action are unknown. METHODS: We addressed these questions in three mouse models of AD with behavioral, electrophysiological, biochemical, and bioinformatic approaches. RESULTS: Long-term UA treatment significantly improved learning, memory, and olfactory function in different AD transgenic mice. UA also reduced amyloid beta (Aß) and tau pathologies and enhanced long-term potentiation. UA induced mitophagy via increasing lysosomal functions. UA improved cellular lysosomal function and normalized lysosomal cathepsins, primarily cathepsin Z, to restore lysosomal function in AD, indicating the critical role of cathepsins in UA-induced therapeutic effects on AD. CONCLUSIONS: Our study highlights the importance of lysosomal dysfunction in AD etiology and points to the high translational potential of UA. HIGHLIGHTS: Long-term urolithin A (UA) treatment improved learning, memory, and olfactory function in Alzheimer's disease (AD) mice. UA restored lysosomal functions in part by regulating cathepsin Z (Ctsz) protein. UA modulates immune responses and AD-specific pathophysiological pathways.
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Doença de Alzheimer , Cumarínicos , Modelos Animais de Doenças , Lisossomos , Camundongos Transgênicos , Mitofagia , Doença de Alzheimer/tratamento farmacológico , Animais , Cumarínicos/farmacologia , Cumarínicos/uso terapêutico , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Camundongos , Mitofagia/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Cognição/efeitos dos fármacosRESUMO
RecQ helicase family proteins play vital roles in maintaining genome stability, including DNA replication, recombination, and DNA repair. In human cells, there are five RecQ helicases: RECQL1, Bloom syndrome (BLM), Werner syndrome (WRN), RECQL4, and RECQL5. Dysfunction or absence of RecQ proteins is associated with genetic disorders, tumorigenesis, premature aging, and neurodegeneration. The biochemical and biological roles of RecQ helicases are rather well established, however, there is no systematic study comparing the behavioral changes among various RecQ-deficient mice including consequences of exposure to DNA damage. Here, we investigated the effects of ionizing irradiation (IR) on three RecQ-deficient mouse models (RecQ1, WRN and RecQ4). We find abnormal cognitive behavior in RecQ-deficient mice in the absence of IR. Interestingly, RecQ dysfunction impairs social ability and induces depressive-like behavior in mice after a single exposure to IR, suggesting that RecQ proteins play roles in mood and cognition behavior. Further, transcriptomic and metabolomic analyses revealed significant alterations in RecQ-deficient mice, especially after IR exposure. In particular, pathways related to neuronal and microglial functions, DNA damage repair, cell cycle, and reactive oxygen responses were downregulated in the RecQ4 and WRN mice. In addition, increased DNA damage responses were found in RecQ-deficient mice. Notably, two genes, Aldolase Fructose-Bisphosphate B (Aldob) and NADPH Oxidase 4 (Nox4), were differentially expressed in RecQ-deficient mice. Our findings suggest that RecQ dysfunction contributes to social and depressive-like behaviors in mice, and that aldolase activity may be associated with these changes, representing a potential therapeutic target.
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Replicação do DNA , RecQ Helicases , Animais , Humanos , Camundongos , RecQ Helicases/genética , RecQ Helicases/metabolismo , Reparo do DNA , Dano ao DNA , Instabilidade Genômica , Aldeído Liases/genética , Aldeído Liases/metabolismoRESUMO
SUMMARY: Pan-genome analyses are routinely carried out for bacteria to interpret the within-species gene presence/absence variations (PAVs). However, pan-genome analyses are rare for eukaryotes due to the large sizes and higher complexities of their genomes. Here we proposed EUPAN, a eukaryotic pan-genome analysis toolkit, enabling automatic large-scale eukaryotic pan-genome analyses and detection of gene PAVs at a relatively low sequencing depth. In the previous studies, we demonstrated the effectiveness and high accuracy of EUPAN in the pan-genome analysis of 453 rice genomes, in which we also revealed widespread gene PAVs among individual rice genomes. Moreover, EUPAN can be directly applied to the current re-sequencing projects primarily focusing on single nucleotide polymorphisms. AVAILABILITY AND IMPLEMENTATION: EUPAN is implemented in Perl, R and C ++. It is supported under Linux and preferred for a computer cluster with LSF and SLURM job scheduling system. EUPAN together with its standard operating procedure (SOP) is freely available for non-commercial use (CC BY-NC 4.0) at http://cgm.sjtu.edu.cn/eupan/index.html . CONTACT: ccwei@sjtu.edu.cn or jianxin.shi@sjtu.edu.cn. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Eucariotos/genética , Genética Populacional/métodos , Genoma , Análise de Sequência de DNA/métodos , Software , Genômica/métodos , Técnicas de Genotipagem/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Polimorfismo de Nucleotídeo ÚnicoRESUMO
It is a consensus in the international manned space field that factors such as microgravity during the space flight can cause anxiety, depression and other important brain function abnormalities in astronauts. However, the neural mechanism at the molecular level is still unclear. Due to the limitations of research conditions, studies of biological changes in the primate brain have been comparatively few. We took advantage of -6° head-down bed rest (HDBR), one of the most implemented space analogues on the ground, to investigate the effects of simulated weightlessness on non-human primate brain metabolites. The Rhesus Macaque monkeys in the experiment were divided into three groups: the control group, the 42-day simulated weightlessness group with HDBR, and the recovery group, which had 28 days of free activity in the home cage after the HDBR. Liquid chromatography-mass spectrometry (LC-MS) was used to perform metabolomics analysis on specific brain areas of the monkeys under three experimental conditions. Our results show that simulated weightlessness can cause neurotransmitter imbalances, the amino acid and energy metabolism disorders, and hormone disturbances. But these metabolomics changes are reversible after recovery. Our study suggests that long-term brain damage in space flight might be reversible at the metabolic level. This lays a technical foundation for ensuring brain health and enhancing the brain function in future space studies.
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Repouso em Cama , Encéfalo , Decúbito Inclinado com Rebaixamento da Cabeça , Macaca mulatta , Simulação de Ausência de Peso , Animais , Encéfalo/metabolismo , Masculino , Metabolômica , Ausência de Peso/efeitos adversos , Neurotransmissores/metabolismo , Aminoácidos/metabolismo , Hormônios/metabolismoRESUMO
There is considerable interest in whether sensory deficiency is associated with the development of Alzheimer's disease (AD). Notably, the relationship between hearing impairment and AD is of high relevance but still poorly understood. In this study, we found early-onset hearing loss in two AD mouse models, 3xTgAD and 3xTgAD/Polß+/-. The 3xTgAD/Polß+/- mouse is DNA repair deficient and has more humanized AD features than the 3xTgAD. Both AD mouse models showed increased auditory brainstem response (ABR) thresholds between 16 and 32 kHz at 4 weeks of age, much earlier than any AD cognitive and behavioral changes. The ABR thresholds were significantly higher in 3xTgAD/Polß+/- mice than in 3xTgAD mice at 16 kHz, and distortion product otoacoustic emission signals were reduced, indicating that DNA damage may be a factor underlying early hearing impairment in AD. Poly ADP-ribosylation and protein expression levels of DNA damage markers increased significantly in the cochlea of the AD mice but not in the adjacent auditory cortex. Phosphoglycerate mutase 2 levels and the number of synaptic ribbons in the presynaptic zones of inner hair cells were decreased in the cochlea of the AD mice. Furthermore, the activity of sirtuin 3 was downregulated in the cochlea of these mice, indicative of impaired mitochondrial function. Taken together, these findings provide new insights into potential mechanisms for hearing dysfunction in AD and suggest that DNA damage in the cochlea might contribute to the development of early hearing loss in AD.
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People with neuropsychiatric disorders such as schizophrenia often display deficits in spatial working memory and attention. Evaluating working memory and attention in schizophrenia patients is usually based on traditional tasks and the interviewer's judgment. We developed a simple Spatial Working Memory and Attention Test on Paired Symbols (SWAPS). It takes only several minutes to complete, comprising 101 trials for each subject. In this study, we tested 72 schizophrenia patients and 188 healthy volunteers in China. In a healthy control group with ages ranging from 12 to 60, the efficiency score (accuracy divided by reaction time) reached a peak in the 20-27 age range and then declined with increasing age. Importantly, schizophrenia patients failed to display this developmental trend in the same age range and adults had significant deficits compared to the control group. Our data suggests that this simple Spatial Working Memory and Attention Test on Paired Symbols can be a useful tool for studies of spatial working memory and attention in neuropsychiatric disorders.
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Atenção/fisiologia , Deficiências do Desenvolvimento/psicologia , Memória de Curto Prazo/fisiologia , Testes Neuropsicológicos , Psicologia do Esquizofrênico , Percepção Espacial/fisiologia , Adolescente , Adulto , Envelhecimento/psicologia , Povo Asiático , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Desempenho Psicomotor/fisiologia , Esquizofrenia , Adulto JovemRESUMO
Aging is accompanied by a decline in DNA repair efficiency, which leads to the accumulation of different types of DNA damage. Age-associated chronic inflammation and generation of reactive oxygen species exacerbate the aging process and age-related chronic disorders. These inflammatory processes establish conditions that favor accumulation of DNA base damage, especially 8-oxo-7,8 di-hydroguanine (8-oxoG), which in turn contributes to various age associated diseases. 8-oxoG is repaired by 8-oxoG glycosylase1 (OGG1) through the base excision repair (BER) pathway. OGG1 is present in both the cell nucleus and in mitochondria. Mitochondrial OGG1 has been implicated in mitochondrial DNA repair and increased mitochondrial function. Using transgenic mouse models and cell lines that have been engineered to have enhanced expression of mitochondria-targeted OGG1 (mtOGG1), we show that elevated levels of mtOGG1 in mitochondria can reverse aging-associated inflammation and improve functions. Old male mtOGG1Tg mice show decreased inflammation response, decreased TNFα levels and multiple pro-inflammatory cytokines. Moreover, we observe that male mtOGG1Tg mice show resistance to STING activation. Interestingly, female mtOGG1Tg mice did not respond to mtOGG1 overexpression. Further, HMC3 cells expressing mtOGG1 display decreased release of mtDNA into the cytoplasm after lipopolysacchride induction and regulate inflammation through the pSTING pathway. Also, increased mtOGG1 expression reduced LPS-induced loss of mitochondrial functions. These results suggest that mtOGG1 regulates age-associated inflammation by controlling release of mtDNA into the cytoplasm.
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DNA Glicosilases , DNA Mitocondrial , Animais , Feminino , Masculino , Camundongos , Dano ao DNA , DNA Glicosilases/genética , DNA Glicosilases/metabolismo , Reparo do DNA , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Inflamação/genética , Inflamação/metabolismo , Camundongos Transgênicos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Doenças Neuroinflamatórias , Estresse Oxidativo/genética , HumanosRESUMO
Olfactory dysfunction is a prevalent symptom and an early marker of age-related neurodegenerative diseases in humans, including Alzheimer's and Parkinson's Diseases. However, as olfactory dysfunction is also a common symptom of normal aging, it is important to identify associated behavioral and mechanistic changes that underlie olfactory dysfunction in nonpathological aging. In the present study, we systematically investigated age-related behavioral changes in four specific domains of olfaction and the molecular basis in C57BL/6J mice. Our results showed that selective loss of odor discrimination was the earliest smelling behavioral change with aging, followed by a decline in odor sensitivity and detection while odor habituation remained in old mice. Compared to behavioral changes related with cognitive and motor functions, smelling loss was among the earliest biomarkers of aging. During aging, metabolites related with oxidative stress, osmolytes, and infection became dysregulated in the olfactory bulb, and G protein coupled receptor-related signaling was significantly down regulated in olfactory bulbs of aged mice. Poly ADP-ribosylation levels, protein expression of DNA damage markers, and inflammation increased significantly in the olfactory bulb of older mice. Lower NAD+ levels were also detected. Supplementation of NAD+ through NR in water improved longevity and partially enhanced olfaction in aged mice. Our studies provide mechanistic and biological insights into the olfaction decline during aging and highlight the role of NAD+ for preserving smelling function and general health.
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Transtornos do Olfato , Olfato , Humanos , Camundongos , Animais , Transtornos do Olfato/diagnóstico , Transtornos do Olfato/patologia , Camundongos Endogâmicos C57BL , NAD/metabolismo , Envelhecimento/patologia , Dano ao DNA , Bulbo Olfatório/metabolismo , Bulbo Olfatório/patologia , Inflamação/metabolismoRESUMO
Adult neurogenesis, the process by which neurons are generated in certain areas of the adult brain, declines in an age-dependent manner and is one potential target for extending cognitive healthspan. Aging is a major risk factor for neurodegenerative diseases and, as lifespans are increasing, these health challenges are becoming more prevalent. An age-associated loss in neural stem cell number and/or activity could cause this decline in brain function, so interventions that reverse aging in stem cells might increase the human cognitive healthspan. In this review, we describe the involvement of adult neurogenesis in neurodegenerative diseases and address the molecular mechanistic aspects of neurogenesis that involve some of the key aggregation-prone proteins in the brain (i.e., tau, Aß, α-synuclein, ). We summarize the research pertaining to interventions that increase neurogenesis and regulate known targets in aging research, such as mTOR and sirtuins. Lastly, we share our outlook on restoring the levels of neurogenesis to physiological levels in elderly individuals and those with neurodegeneration. We suggest that modulating neurogenesis represents a potential target for interventions that could help in the fight against neurodegeneration and cognitive decline.
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Células-Tronco Neurais , Doenças Neurodegenerativas , Idoso , Envelhecimento/fisiologia , Hipocampo/metabolismo , Humanos , Células-Tronco Neurais/fisiologia , Doenças Neurodegenerativas/metabolismo , Neurogênese/fisiologiaRESUMO
Alzheimer's disease (AD) is the most common neurodegenerative disease. Growing evidence suggests an important role for gut dysbiosis and gut microbiota-host interactions in aging and neurodegeneration. Our previous works have demonstrated that supplementation with the nicotinamide adenine dinucleotide (NAD+) precursor, nicotinamide riboside (NR), reduced the brain features of AD, including neuroinflammation, deoxyribonucleic acid (DNA) damage, synaptic dysfunction, and cognitive impairment. However, the impact of NR administration on the intestinal microbiota of AD remains unknown. In this study, we investigated the relationship between gut microbiota and NR treatment in APP/PS1 transgenic (AD) mice. Compared with wild type (WT) mice, the gut microbiota diversity in AD mice was lower and the microbiota composition and enterotype were significantly different. Moreover, there were gender differences in gut microbiome between female and male AD mice. After supplementation with NR for 8 weeks, the decreased diversity and perturbated microbial compositions were normalized in AD mice. This included the species Oscillospira, Butyricicoccus, Desulfovibrio, Bifidobacterium, Olsenella, Adlercreutzia, Bacteroides, Akkermansia, and Lactobacillus. Our results indicate an interplay between NR and host-microbiota in APP/PS1 mice, suggesting that the effect of NR on gut dysbiosis may be an important component in its therapeutic functions in AD.
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The microgravity environment in space can impact astronauts' cognitive and behavioral activities. However, due to the limitations of research conditions, studies of biological changes in the primate brain, such as neurogenesis, have been comparatively few. We take advantage of - 6° head-down bed rest (HDBR), one of the most implemented space analogue on the ground, to investigate the effects of weightlessness on neurogenesis of non-human primate brain. Rhesus Macaque monkeys were subjected to HDBR for 42 days to simulate weightlessness. BrdU (5-bromodeoxyuridin) and IdU (iododeoxyuridine) were intraperitoneally injected separately before or after HDBR to label the survival and proliferation of newborn neurons. Immunohistochemistry was performed to study the effect of simulated weightlessness on neurogenesis. BrdU staining showed that survival of newborn neurons was reduced, while there were fewer BrdU-positive neurons in the HDBR group compared with the control. Furthermore, IdU-positive neurons also decreased in the HDBR group suggesting a reduced proliferation capacity for these newborn neurons. Our results demonstrate the definite neurogenesis in the adult rhesus macaque hippocampus, and simulated weightlessness HDBR procedure impairs the adult neurogenesis.
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Envelhecimento/fisiologia , Repouso em Cama , Hipocampo/fisiologia , Neurogênese , Simulação de Ausência de Peso , Animais , Macaca mulattaRESUMO
Studies have implied that the circadian oscillation of mitogen-activated protein kinase (MAPK) signal pathways is crucial for hippocampus-dependent memory. NF1 mouse models (Nf1 heterozygous null mutants; Nf1 +/-) displayed enhanced MAPK activity in the hippocampus and resulted in memory deficits. We assumed a link between MAPK pathways and hippocampal rhythmic oscillations, which have never been explored in Nf1 +/- mice. We demonstrated that the level of extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation in Nf1 +/- mice were significantly higher at nighttime than at daytime. Moreover, the in vivo recording revealed that for the Nf1 +/- group, the power spectral density of theta rhythm significantly decreased and the firing rates of pyramidal neurons increased. Our results indicated that the hippocampal MAPK oscillation and theta rhythmic oscillations in Nf1 +/- mice were disturbed and hinted about a possible mechanism for the brain dysfunction in Nf1 +/- mice.
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Ritmo Circadiano , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hipocampo/enzimologia , Hipocampo/fisiopatologia , Neurofibromina 1/genética , Ritmo Teta/fisiologia , Potenciais de Ação/fisiologia , Animais , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , FosforilaçãoRESUMO
There is an increasing risk of mental disorders, such as acute stress disorder (ASD), post-traumatic stress disorder (PTSD) and depression among survivors who were trapped in rubble during earthquake. Such long-term impaction of a single acute restraint stress has not been extensively explored. In this study, we subjected mice to 24-hour-restraint to simulate the trapping episode, and investigated the acute (2 days after the restraint) and long-term (35 days after the restraint) impacts. Surprisingly, we found that the mice displayed depression-like behaviors, decreased glucose uptake in brain and reduced adult hippocampal neurogenesis 35 days after the restraint. Differential expression profiling based on microarrays suggested that genes and pathways related to depression and other mental disorders were differentially expressed in both PFC and hippocampus. Furthermore, the depression-like phenotypes induced by 24-hour-restraint could be reversed by fluoxetine, a type of antidepressant drug. These findings demonstrated that a single severe stressful event could produce long-term depressive-like phenotypes. Moreover, the 24-hour-restraint stress mice could also be used for further studies on mood disorders.
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Comportamento Animal , Encéfalo/fisiopatologia , Depressão/etiologia , Depressão/patologia , Animais , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Camundongos , Restrição FísicaRESUMO
BACKGROUND: Studies have indicated that depressive disorders are observed frequently in dentists. It's suggested that dentists encounter numerous sources of stress in their professional career. We noticed that the noises in dental environments are very unpleasant. The animal modeling studies suggested that stressful noise could produce depressive-like phenotypes in rodent animals. We hypothesize that the dental noise may be one of the primary stressors causing depressive disorders in dentists. RESULTS: We treated C57BL/6 mice with programmatically played wide-spectrum dental noise for 8 h/day at 75 ± 10 dB SPL level for 30 days, and then tested the behaviors. After exposure to dental noise, animals displayed the depressive-like phenotypes, accompanied by inhibition of neurogenesis in hippocampus. These deficits were ameliorated by orally administered with antidepressant fluoxetine. CONCLUSIONS: Our results suggested that dental noise could be one of the primary stressors for the pathogenesis of depressive disorders and the dental noise mouse model could be used in further depression studies.
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Odontologia , Depressão/etiologia , Ruído/efeitos adversos , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Comportamento Animal , Comportamento de Escolha , Depressão/complicações , Depressão/tratamento farmacológico , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Masculino , Camundongos Endogâmicos C57BL , Neurogênese/efeitos dos fármacos , Fenótipo , Estresse Psicológico/complicações , Estresse Psicológico/tratamento farmacológico , Sacarose , Aumento de Peso/efeitos dos fármacosRESUMO
Biological and biomedical research relies on comprehensive understanding of protein-coding transcripts. However, the total number of human proteins is still unknown due to the prevalence of alternative splicing. In this paper, we detected 31,566 novel transcripts with coding potential by filtering our ab initio predictions with 50 RNA-seq datasets from diverse tissues/cell lines. PCR followed by MiSeq sequencing showed that at least 84.1% of these predicted novel splice sites could be validated. In contrast to known transcripts, the expression of these novel transcripts were highly tissue-specific. Based on these novel transcripts, at least 36 novel proteins were detected from shotgun proteomics data of 41 breast samples. We also showed L1 retrotransposons have a more significant impact on the origin of new transcripts/genes than previously thought. Furthermore, we found that alternative splicing is extraordinarily widespread for genes involved in specific biological functions like protein binding, nucleoside binding, neuron projection, membrane organization and cell adhesion. In the end, the total number of human transcripts with protein-coding potential was estimated to be at least 204,950.