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1.
J Neurosci ; 42(33): 6453-6468, 2022 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-35835549

RESUMO

Individuals who have Down syndrome (DS) frequently develop early onset Alzheimer's disease (AD), a neurodegenerative condition caused by the buildup of aggregated amyloid-ß (Aß) and tau proteins in the brain. Aß is produced by amyloid precursor protein (APP), a gene located on chromosome 21. People who have DS have three copies of chromosome 21 and thus also an additional copy of APP; this genetic change drives the early development of AD in these individuals. Here we use a combination of next-generation mouse models of DS (Tc1, Dp3Tyb, Dp(10)2Yey and Dp(17)3Yey) and a knockin mouse model of Aß accumulation (AppNL-F ) to determine how chromosome 21 genes, other than APP, modulate APP/Aß in the brain when in three copies. Using both male and female mice, we demonstrate that three copies of other chromosome 21 genes are sufficient to partially ameliorate Aß accumulation in the brain. We go on to identify a subregion of chromosome 21 that contains the gene(s) causing this decrease in Aß accumulation and investigate the role of two lead candidate genes, Dyrk1a and Bace2 Thus, an additional copy of chromosome 21 genes, other than APP, can modulate APP/Aß in the brain under physiological conditions. This work provides critical mechanistic insight into the development of disease and an explanation for the typically later age of onset of dementia in people who have AD in DS, compared with those who have familial AD caused by triplication of APP SIGNIFICANCE STATEMENT Trisomy of chromosome 21 is a commonly occurring genetic risk factor for early-onset Alzheimer's disease (AD), which has been previously attributed to people with Down syndrome having three copies of the amyloid precursor protein (APP) gene, which is encoded on chromosome 21. However, we have shown that an extra copy of other chromosome 21 genes modifies AD-like phenotypes independently of APP copy number (Wiseman et al., 2018; Tosh et al., 2021). Here, we use a mapping approach to narrow down the genetic cause of the modulation of pathology, demonstrating that gene(s) on chromosome 21 decrease Aß accumulation in the brain, independently of alterations to full-length APP or C-terminal fragment abundance and that just 38 genes are sufficient to cause this.


Assuntos
Doença de Alzheimer , Síndrome de Down , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Síndrome de Down/complicações , Síndrome de Down/genética , Feminino , Humanos , Masculino , Camundongos
2.
Mamm Genome ; 32(2): 94-103, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33713180

RESUMO

The small EDRK-rich factor 2 (SERF2) is a highly conserved protein that modifies amyloid fibre assembly in vitro and promotes protein misfolding. However, the role of SERF2 in regulating age-related proteotoxicity remains largely unexplored due to a lack of in vivo models. Here, we report the generation of Serf2 knockout mice using an ES cell targeting approach, with Serf2 knockout alleles being bred onto different defined genetic backgrounds. We highlight phenotyping data from heterozygous Serf2+/- mice, including unexpected male-specific phenotypes in startle response and pre-pulse inhibition. We report embryonic lethality in Serf2-/- null animals when bred onto a C57BL/6 N background. However, homozygous null animals were viable on a mixed genetic background and, remarkably, developed without obvious abnormalities. The Serf2 knockout mice provide a powerful tool to further investigate the role of SERF2 protein in previously unexplored pathophysiological pathways in the context of a whole organism.


Assuntos
Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fenótipo , Fatores Etários , Alelos , Processamento Alternativo , Animais , Linhagem Celular , Modelos Animais de Doenças , Células-Tronco Embrionárias/metabolismo , Feminino , Regulação da Expressão Gênica , Estudos de Associação Genética/métodos , Patrimônio Genético , Loci Gênicos , Genótipo , Masculino , Camundongos , Camundongos Knockout , Especificidade de Órgãos , Microtomografia por Raio-X
3.
Neuroimage ; 223: 117271, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32835824

RESUMO

Down Syndrome is a chromosomal disorder that affects the development of cerebellar cortical lobules. Impaired neurogenesis in the cerebellum varies among different types of neuronal cells and neuronal layers. In this study, we developed an imaging analysis framework that utilizes gadolinium-enhanced ex vivo mouse brain MRI. We extracted the middle Purkinje layer of the mouse cerebellar cortex, enabling the estimation of the volume, thickness, and surface area of the entire cerebellar cortex, the internal granular layer, and the molecular layer in the Tc1 mouse model of Down Syndrome. The morphometric analysis of our method revealed that a larger proportion of the cerebellar thinning in this model of Down Syndrome resided in the inner granule cell layer, while a larger proportion of the surface area shrinkage was in the molecular layer.


Assuntos
Córtex Cerebelar/diagnóstico por imagem , Córtex Cerebelar/patologia , Síndrome de Down/diagnóstico por imagem , Síndrome de Down/patologia , Imageamento por Ressonância Magnética/métodos , Neurônios/patologia , Animais , Meios de Contraste , Modelos Animais de Doenças , Gadolínio/administração & dosagem , Aumento da Imagem/métodos , Masculino , Camundongos Endogâmicos C57BL , Coloração e Rotulagem/métodos
4.
Nat Rev Neurosci ; 16(9): 564-74, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26243569

RESUMO

Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP)--an Alzheimer disease risk factor--although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in people with Down syndrome could provide insights into the mechanisms that cause dementia in the general population.


Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Síndrome de Down/diagnóstico , Síndrome de Down/genética , Predisposição Genética para Doença/genética , Doença de Alzheimer/etiologia , Peptídeos beta-Amiloides/genética , Humanos
5.
Brain ; 141(8): 2457-2474, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29945247

RESUMO

Down syndrome, caused by trisomy of chromosome 21, is the single most common risk factor for early-onset Alzheimer's disease. Worldwide approximately 6 million people have Down syndrome, and all these individuals will develop the hallmark amyloid plaques and neurofibrillary tangles of Alzheimer's disease by the age of 40 and the vast majority will go on to develop dementia. Triplication of APP, a gene on chromosome 21, is sufficient to cause early-onset Alzheimer's disease in the absence of Down syndrome. However, whether triplication of other chromosome 21 genes influences disease pathogenesis in the context of Down syndrome is unclear. Here we show, in a mouse model, that triplication of chromosome 21 genes other than APP increases amyloid-ß aggregation, deposition of amyloid-ß plaques and worsens associated cognitive deficits. This indicates that triplication of chromosome 21 genes other than APP is likely to have an important role to play in Alzheimer's disease pathogenesis in individuals who have Down syndrome. We go on to show that the effect of trisomy of chromosome 21 on amyloid-ß aggregation correlates with an unexpected shift in soluble amyloid-ß 40/42 ratio. This alteration in amyloid-ß isoform ratio occurs independently of a change in the carboxypeptidase activity of the γ-secretase complex, which cleaves the peptide from APP, or the rate of extracellular clearance of amyloid-ß. These new mechanistic insights into the role of triplication of genes on chromosome 21, other than APP, in the development of Alzheimer's disease in individuals who have Down syndrome may have implications for the treatment of this common cause of neurodegeneration.


Assuntos
Síndrome de Down/genética , Síndrome de Down/patologia , Placa Amiloide/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/fisiologia , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Emaranhados Neurofibrilares/patologia , Placa Amiloide/patologia , Trissomia
6.
J Virol ; 89(9): 4738-47, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25673720

RESUMO

UNLABELLED: The risk of transmission of transmissible spongiform encephalopathies (TSE) between different species has been notoriously unpredictable because the mechanisms of transmission are not fully understood. A transmission barrier between species often prevents infection of a new host with a TSE agent. Nonetheless, some TSE agents are able to cross this barrier and infect new species, with devastating consequences. The host PrP(C) misfolds during disease pathogenesis and has a major role in controlling the transmission of agents between species, but sequence compatibility between host and agent PrP(C) does not fully explain host susceptibility. PrP(C) is posttranslationally modified by the addition of glycan moieties which have an important role in the infectious process. Here, we show in vivo that glycosylation of the host PrP(C) has a significant impact on the transmission of TSE between different host species. We infected mice carrying different glycosylated forms of PrP(C) with two human agents (sCJDMM2 and vCJD) and one hamster strain (263K). The absence of glycosylation at both or the first PrP(C) glycosylation site in the host results in almost complete resistance to disease. The absence of the second site of N-glycan has a dramatic effect on the barrier to transmission between host species, facilitating the transmission of sCJDMM2 to a host normally resistant to this agent. These results highlight glycosylation of PrP(C) as a key factor in determining the transmission efficiency of TSEs between different species. IMPORTANCE: The risks of transmission of TSE between different species are difficult to predict due to a lack of knowledge over the mechanisms of disease transmission; some strains of TSE are able to cross a species barrier, while others do not. The host protein, PrP(C), plays a major role in disease transmission. PrP(C) undergoes posttranslational glycosylation, and the addition of these glycans may play a role in disease transmission. We infected mice that express different forms of glycosylated PrP(C) with three different TSE agents. We demonstrate that changing the glycosylation status of the host can have profound effects on disease transmission, changing host susceptibility and incubation times. Our results show that PrP(C) glycosylation is a key factor in determining risks of TSE transmission between species.


Assuntos
Glicosilação , Polissacarídeos/análise , Proteínas PrPC/metabolismo , Doenças Priônicas/transmissão , Doenças Priônicas/veterinária , Animais , Cricetinae , Resistência à Doença , Suscetibilidade a Doenças , Feminino , Humanos , Masculino , Camundongos
7.
Neurobiol Learn Mem ; 130: 118-28, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26868479

RESUMO

The present study examined memory function in Tc1 mice, a transchromosomic model of Down syndrome (DS). Tc1 mice demonstrated an unusual delay-dependent deficit in recognition memory. More specifically, Tc1 mice showed intact immediate (30sec), impaired short-term (10-min) and intact long-term (24-h) memory for objects. A similar pattern was observed for olfactory stimuli, confirming the generality of the pattern across sensory modalities. The specificity of the behavioural deficits in Tc1 mice was confirmed using APP overexpressing mice that showed the opposite pattern of object memory deficits. In contrast to object memory, Tc1 mice showed no deficit in either immediate or long-term memory for object-in-place information. Similarly, Tc1 mice showed no deficit in short-term memory for object-location information. The latter result indicates that Tc1 mice were able to detect and react to spatial novelty at the same delay interval that was sensitive to an object novelty recognition impairment. These results demonstrate (1) that novelty detection per se and (2) the encoding of visuo-spatial information was not disrupted in adult Tc1 mice. The authors conclude that the task specific nature of the short-term recognition memory deficit suggests that the trisomy of genes on human chromosome 21 in Tc1 mice impacts on (perirhinal) cortical systems supporting short-term object and olfactory recognition memory.


Assuntos
Síndrome de Down/psicologia , Transtornos da Memória/psicologia , Memória de Longo Prazo/fisiologia , Memória de Curto Prazo/fisiologia , Reconhecimento Psicológico/fisiologia , Animais , Modelos Animais de Doenças , Síndrome de Down/genética , Comportamento Exploratório/fisiologia , Feminino , Masculino , Transtornos da Memória/genética , Camundongos , Comportamento Espacial/fisiologia
8.
Hum Mol Genet ; 22(9): 1709-24, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23349361

RESUMO

Tc1 mouse model of Down syndrome (DS) is functionally trisomic for ∼120 human chromosome 21 (HSA21) classical protein-coding genes. Tc1 mice display features relevant to the DS phenotype, including abnormalities in learning and memory and synaptic plasticity. To determine the molecular basis for the phenotypic features, the levels of 90 phosphorylation-specific and phosphorylation-independent proteins were measured by Reverse Phase Protein Arrays in hippocampus and cortex, and 64 in cerebellum, of Tc1 mice and littermate controls. Abnormal levels of proteins involved in MAP kinase, mTOR, GSK3B and neuregulin signaling were identified in trisomic mice. In addition, altered correlations among the levels of N-methyl-D-aspartate (NMDA) receptor subunits and the HSA21 proteins amyloid beta (A4) precursor protein (APP) and TIAM1, and between immediate early gene (IEG) proteins and the HSA21 protein superoxide dismutase-1 (SOD1) were found in the hippocampus of Tc1 mice, suggesting altered stoichiometry among these sets of functionally interacting proteins. Protein abnormalities in Tc1 mice were compared with the results of a similar analysis of Ts65Dn mice, a DS mouse model that is trisomic for orthologs of 50 genes trisomic in the Tc1 plus an additional 38 HSA21 orthologs. While there are similarities, abnormalities unique to the Tc1 include increased levels of the S100B calcium-binding protein, mTOR proteins RAPTOR and P70S6, the AMP-kinase catalytic subunit AMPKA, the IEG proteins FBJ murine osteosarcoma viral oncogene homolog (CFOS) and activity-regulated cytoskeleton-associated protein (ARC), and the neuregulin 1 receptor ERBB4. These data identify novel perturbations, relevant to neurological function and to some seen in Alzheimer's disease, that may occur in the DS brain, potentially contributing to phenotypic features and influencing drug responses.


Assuntos
Encéfalo/fisiopatologia , Síndrome de Down/genética , Perfilação da Expressão Gênica , Proteínas de Neoplasias/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Encéfalo/metabolismo , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Modelos Animais de Doenças , Síndrome de Down/metabolismo , Síndrome de Down/fisiopatologia , Feminino , Regulação da Expressão Gênica , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/metabolismo , Fosforilação , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Proteína Regulatória Associada a mTOR , Subunidade beta da Proteína Ligante de Cálcio S100 , Proteínas S100/genética , Proteínas S100/metabolismo , Proteína 1 Indutora de Invasão e Metástase de Linfoma de Células T , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
9.
Proc Natl Acad Sci U S A ; 109(34): 13722-7, 2012 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-22869728

RESUMO

Prion diseases are fatal neurodegenerative disorders that include bovine spongiform encephalopathy (BSE) and scrapie in animals and Creutzfeldt-Jakob disease (CJD) in humans. They are characterized by long incubation periods, variation in which is determined by many factors including genetic background. In some cases it is possible that incubation time may be directly correlated to the level of gene expression. To test this hypothesis, we combined incubation time data from five different inbred lines of mice with quantitative gene expression profiling in normal brains and identified five genes with expression levels that correlate with incubation time. One of these genes, Hspa13 (Stch), is a member of the Hsp70 family of ATPase heat shock proteins, which have been previously implicated in prion propagation. To test whether Hspa13 plays a causal role in determining the incubation period, we tested two overexpressing mouse models. The Tc1 human chromosome 21 (Hsa21) transchromosomic mouse model of Down syndrome is trisomic for many Hsa21 genes including Hspa13 and following Chandler/Rocky Mountain Laboratory (RML) prion inoculation, shows a 4% reduction in incubation time. Furthermore, a transgenic model with eightfold overexpression of mouse Hspa13 exhibited highly significant reductions in incubation time of 16, 15, and 7% following infection with Chandler/RML, ME7, and MRC2 prion strains, respectively. These data further implicate Hsp70-like molecular chaperones in protein misfolding disorders such as prion disease.


Assuntos
Regulação da Expressão Gênica , Proteínas de Choque Térmico HSP70/biossíntese , Proteínas de Choque Térmico HSP70/fisiologia , Doenças Priônicas/genética , Adenosina Trifosfatases/química , Animais , Proteínas de Choque Térmico HSP70/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Transgênicos , Modelos Genéticos , Neurônios/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Príons/metabolismo , RNA Complementar/metabolismo
10.
Hum Mol Genet ; 21(19): 4162-70, 2012 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-22736031

RESUMO

In multicellular organisms, developmental changes to replication timing occur in 400-800 kb domains across half the genome. While examples of epigenetic control of replication timing have been described, a role for DNA sequence in mammalian replication-timing regulation has not been substantiated. To assess the role of DNA sequences in directing developmental changes to replication timing, we profiled replication timing in mice carrying a genetically rearranged Human Chromosome 21 (Hsa21). In two distinct mouse cell types, Hsa21 sequences maintained human-specific replication timing, except at points of Hsa21 rearrangement. Changes in replication timing at rearrangements extended up to 900 kb and consistently reconciled with the wild-type replication pattern at developmental boundaries of replication-timing domains. Our results are consistent with DNA sequence-driven regulation of Hsa21 replication timing during development and provide evidence that mammalian chromosomes consist of multiple independent units of replication-timing regulation.


Assuntos
Cromossomos Humanos Par 21/genética , Replicação do DNA , Regulação da Expressão Gênica , Rearranjo Gênico , Camundongos/genética , Animais , Linhagem Celular , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Especificidade da Espécie
11.
Acta Neuropathol Commun ; 11(1): 132, 2023 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-37580797

RESUMO

Cathepsin B is a cysteine protease that is implicated in multiple aspects of Alzheimer's disease pathogenesis. The endogenous inhibitor of this enzyme, cystatin B (CSTB) is encoded on chromosome 21. Thus, individuals who have Down syndrome, a genetic condition caused by having an additional copy of chromosome 21, have an extra copy of an endogenous inhibitor of the enzyme. Individuals who have Down syndrome are also at significantly increased risk of developing early-onset Alzheimer's disease (EOAD). The impact of the additional copy of CSTB on Alzheimer's disease development in people who have Down syndrome is not well understood. Here we compared the biology of cathepsin B and CSTB in individuals who had Down syndrome and Alzheimer's disease, with disomic individuals who had Alzheimer's disease or were ageing healthily. We find that the activity of cathepsin B enzyme is decreased in the brain of people who had Down syndrome and Alzheimer's disease compared with disomic individuals who had Alzheimer's disease. This change occurs independently of an alteration in the abundance of the mature enzyme or the number of cathepsin B+ cells. We find that the abundance of CSTB is significantly increased in the brains of individuals who have Down syndrome and Alzheimer's disease compared to disomic individuals both with and without Alzheimer's disease. In mouse and human cellular preclinical models of Down syndrome, three-copies of CSTB increases CSTB protein abundance but this is not sufficient to modulate cathepsin B activity. EOAD and Alzheimer's disease-Down syndrome share many overlapping mechanisms but differences in disease occur in individuals who have trisomy 21. Understanding this biology will ensure that people who have Down syndrome access the most appropriate Alzheimer's disease therapeutics and moreover will provide unique insight into disease pathogenesis more broadly.


Assuntos
Doença de Alzheimer , Síndrome de Down , Humanos , Camundongos , Animais , Síndrome de Down/patologia , Doença de Alzheimer/patologia , Cistatina B/genética , Catepsina B , Microglia/metabolismo
12.
ScientificWorldJournal ; 2012: 214078, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22262951

RESUMO

Abnormalities of chromosome copy number are called aneuploidies and make up a large health load on the human population. Many aneuploidies are lethal because the resulting abnormal gene dosage is highly deleterious. Nevertheless, some whole chromosome aneuploidies can lead to live births. Alterations in the copy number of sections of chromosomes, which are also known as segmental aneuploidies, are also associated with deleterious effects. Here we examine how aneuploidy of whole chromosomes and segmental aneuploidy of chromosomal regions are modeled in the mouse. These models provide a whole animal system in which we aim to investigate the complex phenotype-genotype interactions that arise from alteration in the copy number of genes. Although our understanding of this subject is still in its infancy, already research in mouse models is highlighting possible therapies that might help alleviate the cognitive effects associated with changes in gene number. Thus, creating and studying mouse models of aneuploidy and copy number variation is important for understanding what it is to be human, in both the normal and genomically altered states.


Assuntos
Aneuploidia , Transtornos Cromossômicos/genética , Modelos Animais de Doenças , Camundongos , Animais
13.
Front Neurosci ; 16: 909669, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35747206

RESUMO

There are an estimated 6 million people with Down syndrome (DS) worldwide. In developed countries, the vast majority of these individuals will develop Alzheimer's disease neuropathology characterized by the accumulation of amyloid-ß (Aß) plaques and tau neurofibrillary tangles within the brain, which leads to the early onset of dementia (AD-DS) and reduced life-expectancy. The mean age of onset of clinical dementia is ~55 years and by the age of 80, approaching 100% of individuals with DS will have a dementia diagnosis. DS is caused by trisomy of chromosome 21 (Hsa21) thus an additional copy of a gene(s) on the chromosome must cause the development of AD neuropathology and dementia. Indeed, triplication of the gene APP which encodes the amyloid precursor protein is sufficient and necessary for early onset AD (EOAD), both in people who have and do not have DS. However, triplication of other genes on Hsa21 leads to profound differences in neurodevelopment resulting in intellectual disability, elevated incidence of epilepsy and perturbations to the immune system. This different biology may impact on how AD neuropathology and dementia develops in people who have DS. Indeed, genes on Hsa21 other than APP when in three-copies can modulate AD-pathogenesis in mouse preclinical models. Understanding this biology better is critical to inform drug selection for AD prevention and therapy trials for people who have DS. Here we will review rodent preclinical models of AD-DS and how these can be used for both in vivo and ex vivo (cultured cells and organotypic slice cultures) studies to understand the mechanisms that contribute to the early development of AD in people who have DS and test the utility of treatments to prevent or delay the development of disease.

14.
Neuronal Signal ; 6(1): NS20210054, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35449591

RESUMO

Down syndrome (DS) is the most common chromosomal abnormality and leads to intellectual disability, increased risk of cardiac defects, and an altered immune response. Individuals with DS have an extra full or partial copy of chromosome 21 (trisomy 21) and are more likely to develop early-onset Alzheimer's disease (AD) than the general population. Changes in expression of human chromosome 21 (Hsa21)-encoded genes, such as amyloid precursor protein (APP), play an important role in the pathogenesis of AD in DS (DS-AD). However, the mechanisms of DS-AD remain poorly understood. To date, several mouse models with an extra copy of genes syntenic to Hsa21 have been developed to characterise DS-AD-related phenotypes. Nonetheless, due to genetic and physiological differences between mouse and human, mouse models cannot faithfully recapitulate all features of DS-AD. Cells differentiated from human-induced pluripotent stem cells (iPSCs), isolated from individuals with genetic diseases, can be used to model disease-related cellular and molecular pathologies, including DS. In this review, we will discuss the limitations of mouse models of DS and how these can be addressed using recent advancements in modelling DS using human iPSCs and iPSC-mouse chimeras, and potential applications of iPSCs in preclinical studies for DS-AD.

15.
PLoS One ; 17(5): e0262558, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35544526

RESUMO

Individuals who have Down syndrome (trisomy 21) are at greatly increased risk of developing Alzheimer's disease, characterised by the accumulation in the brain of amyloid-ß plaques. Amyloid-ß is a product of the processing of the amyloid precursor protein, encoded by the APP gene on chromosome 21. In Down syndrome the first site of amyloid-ß accumulation is within endosomes, and changes to endosome biology occur early in Alzheimer's disease. Here, we determine if primary mouse embryonic fibroblasts isolated from a mouse model of Down syndrome can be used to study endosome and APP cell biology. We report that in this cellular model, endosome number, size and APP processing are not altered, likely because APP is not dosage sensitive in the model, despite three copies of App.


Assuntos
Doença de Alzheimer , Síndrome de Down , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Biologia , Síndrome de Down/genética , Síndrome de Down/metabolismo , Endossomos/metabolismo , Fibroblastos/metabolismo , Camundongos , Placa Amiloide/metabolismo
16.
Neuroimage ; 56(3): 974-83, 2011 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-21310249

RESUMO

Extensive worldwide efforts are underway to produce knockout mice for each of the ~25,000 mouse genes, which may give new insights into the underlying pathophysiology of neurological disease. Microscopic magnetic resonance imaging (µMRI) is a key method for non-invasive morphological phenotyping, capable of producing high-resolution 3D images of ex-vivo brains, after fixation with an MR contrast agent. These agents have been suggested to act as active-stains, enhancing structures not normally visible on MRI. In this study, we investigated the structural correlates of the MRI agent Gd-DTPA, together with the optimal preparation and scan parameters for contrast-enhanced gradient-echo imaging of the mouse brain. We observed that in-situ preparation was preferential to ex-situ due to the degree of extraction damage. In-situ brains scanned with optimised parameters, enabled images with a high signal-to-noise-ratio (SNR ~30) and comprehensive anatomical delineation. Direct correlation of the MR brain structures to histology, detailed fine histoarchitecture in the cortex, cerebellum, olfactory bulb and hippocampus. Neurofilament staining demonstrated that regions of negative MR contrast strongly correlated to myelinated white-matter structures, whilst structures of more positive MR contrast corresponded to areas with high grey matter content. We were able to identify many sub-regions, particularly within the hippocampus, such as the unmyelinated mossy fibres (stratum lucidum) and their region of synapse in the stratum pyramidale, together with the granular layer of the dentate gyrus, an area of densely packed cell bodies, which was clearly visible as a region of hyperintensity. This suggests that cellular structure influences the site-specific distribution of the MR contrast agent, resulting in local variations in T(2)*, which leads to enhanced tissue discrimination. Our findings provide insights not only into the cellular distribution and mechanism of MR active-staining, but also allow for three dimensional analysis, which enables interpretation of magnetic resonance microscopy brain data and highlights cellular structure for investigation of disease processes in development and disease.


Assuntos
Encéfalo/anatomia & histologia , Animais , Cerebelo/anatomia & histologia , Córtex Cerebral/anatomia & histologia , Imagem Ecoplanar , Feminino , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Perfusão , Coloração e Rotulagem , Tálamo/anatomia & histologia , Fixação de Tecidos
17.
Hum Mol Genet ; 18(R1): R75-83, 2009 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-19297404

RESUMO

Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and is associated with a number of deleterious phenotypes, including learning disability, heart defects, early-onset Alzheimer's disease and childhood leukaemia. Individuals with DS are affected by these phenotypes to a variable extent; understanding the cause of this variation is a key challenge. Here, we review recent research progress in DS, both in patients and relevant animal models. In particular, we highlight exciting advances in therapy to improve cognitive function in people with DS and the significant developments in understanding the gene content of Hsa21. Moreover, we discuss future research directions in light of new technologies. In particular, the use of chromosome engineering to generate new trisomic mouse models and large-scale studies of genotype-phenotype relationships in patients are likely to significantly contribute to the future understanding of DS.


Assuntos
Cromossomos Humanos Par 21 , Síndrome de Down/tratamento farmacológico , Síndrome de Down/fisiopatologia , Animais , Cognição/efeitos dos fármacos , Síndrome de Down/genética , Humanos
18.
PLoS One ; 16(7): e0242236, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34292972

RESUMO

People with Down syndrome (DS), caused by trisomy of chromosome 21 have a greatly increased risk of developing Alzheimer's disease (AD). This is in part because of triplication of a chromosome 21 gene, APP. This gene encodes amyloid precursor protein, which is cleaved to form amyloid-ß that accumulates in the brains of people who have AD. Recent experimental results demonstrate that a gene or genes on chromosome 21, other than APP, when triplicated significantly accelerate amyloid-ß pathology in a transgenic mouse model of amyloid-ß deposition. Multiple lines of evidence indicate that cysteine cathepsin activity influences APP cleavage and amyloid-ß accumulation. Located on human chromosome 21 (Hsa21) is an endogenous inhibitor of cathepsin proteases, CYSTATIN B (CSTB) which is proposed to regulate cysteine cathepsin activity in vivo. Here we determined if three copies of the mouse gene Cstb is sufficient to modulate amyloid-ß accumulation and cathepsin activity in a transgenic APP mouse model. Duplication of Cstb resulted in an increase in transcriptional and translational levels of Cstb in the mouse cortex but had no effect on the deposition of insoluble amyloid-ß plaques or the levels of soluble or insoluble amyloid-ß42, amyloid-ß40, or amyloid-ß38 in 6-month old mice. In addition, the increased CSTB did not alter the activity of cathepsin B enzyme in the cortex of 3-month or 6-month old mice. These results indicate that the single-gene duplication of Cstb is insufficient to elicit a disease-modifying phenotype in the dupCstb x tgAPP mice, underscoring the complexity of the genetic basis of AD-DS and the importance of multiple gene interactions in disease.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Catepsina B/metabolismo , Cistatina B/genética , Envelhecimento , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Córtex Cerebral/enzimologia , Córtex Cerebral/metabolismo , Cistatina B/metabolismo , Modelos Animais de Doenças , Feminino , Duplicação Gênica , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
19.
Sci Rep ; 11(1): 5736, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33707583

RESUMO

Individuals who have Down syndrome (caused by trisomy of chromosome 21), have a greatly elevated risk of early-onset Alzheimer's disease, in which amyloid-ß accumulates in the brain. Amyloid-ß is a product of the chromosome 21 gene APP (amyloid precursor protein) and the extra copy or 'dose' of APP is thought to be the cause of this early-onset Alzheimer's disease. However, other chromosome 21 genes likely modulate disease when in three-copies in people with Down syndrome. Here we show that an extra copy of chromosome 21 genes, other than APP, influences APP/Aß biology. We crossed Down syndrome mouse models with partial trisomies, to an APP transgenic model and found that extra copies of subgroups of chromosome 21 gene(s) modulate amyloid-ß aggregation and APP transgene-associated mortality, independently of changing amyloid precursor protein abundance. Thus, genes on chromosome 21, other than APP, likely modulate Alzheimer's disease in people who have Down syndrome.


Assuntos
Peptídeos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Síndrome de Down/genética , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/química , Animais , Encéfalo/patologia , Cromossomos de Mamíferos/genética , Modelos Animais de Doenças , Síndrome de Down/complicações , Camundongos , Camundongos Transgênicos , Fenótipo , Fosfotransferases/metabolismo , Agregados Proteicos , Proteína-Arginina N-Metiltransferases/metabolismo , Duplicações Segmentares Genômicas , Convulsões/complicações , Convulsões/patologia , Solubilidade , Análise de Sobrevida , Transgenes
20.
J Negat Results Biomed ; 9: 7, 2010 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-20727138

RESUMO

BACKGROUND: Down syndrome (DS) is caused by trisomy of all or part of chromosome 21. To further understanding of DS we are working with a mouse model, the Tc1 mouse, which carries most of human chromosome 21 in addition to the normal mouse chromosome complement. This mouse is a model for human DS and recapitulates many of the features of the human syndrome such as specific heart defects, and cerebellar neuronal loss. The Tc1 mouse is mosaic for the human chromosome such that not all cells in the model carry it. Thus to help our investigations we aimed to develop a method to identify cells that carry human chromosome 21 in the Tc1 mouse. To this end, we have generated a panel of antibodies raised against proteins encoded by genes on human chromosome 21 that are known to be expressed in the adult brain of Tc1 mice RESULTS: We attempted to generate human specific antibodies against proteins encoded by human chromosome 21. We selected proteins that are expressed in the adult brain of Tc1 mice and contain regions of moderate/low homology with the mouse ortholog. We produced antibodies to seven human chromosome 21 encoded proteins. Of these, we successfully generated three antibodies that preferentially recognise human compared with mouse SOD1 and RRP1 proteins on western blots. However, these antibodies did not specifically label cells which carry a freely segregating copy of Hsa21 in the brains of our Tc1 mouse model of DS. CONCLUSIONS: Although we have successfully isolated new antibodies to SOD1 and RRP1 for use on western blots, in our hands these antibodies have not been successfully used for immunohistochemistry studies. These antibodies are freely available to other researchers. Our data high-light the technical difficulty of producing species-specific antibodies for both western blotting and immunohistochemistry.


Assuntos
Anticorpos/imunologia , Cromossomos Humanos Par 21/genética , Técnicas Imunológicas , Proteínas/genética , Proteínas/imunologia , Envelhecimento/genética , Animais , Especificidade de Anticorpos/imunologia , Western Blotting , Encéfalo/metabolismo , Cromatografia de Afinidade , Modelos Animais de Doenças , Síndrome de Down/genética , Síndrome de Down/imunologia , Regulação da Expressão Gênica , Humanos , Imunização , Camundongos , Coelhos , Trissomia/genética , Trissomia/imunologia
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