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  1. Article: Rodent Modeling of Alzheimer's Disease in Down Syndrome:

    Farrell, Clíona / Mumford, Paige / Wiseman, Frances K

    Frontiers in neuroscience

    2022  Volume 16, Page(s) 909669

    Abstract: 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-β (Aβ) plaques and tau ... ...

    Abstract 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-β (Aβ) 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
    Language English
    Publishing date 2022-06-07
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2411902-7
    ISSN 1662-453X ; 1662-4548
    ISSN (online) 1662-453X
    ISSN 1662-4548
    DOI 10.3389/fnins.2022.909669
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Cell models for Down syndrome-Alzheimer's disease research.

    Wu, Yixing / West, Nicole R / Bhattacharyya, Anita / Wiseman, Frances K

    Neuronal signaling

    2022  Volume 6, Issue 1, Page(s) NS20210054

    Abstract: 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) ... ...

    Abstract 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 (
    Language English
    Publishing date 2022-04-08
    Publishing country England
    Document type Journal Article ; Review
    ISSN 2059-6553
    ISSN (online) 2059-6553
    DOI 10.1042/NS20210054
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Endosomal structure and APP biology are not altered in a preclinical mouse cellular model of Down syndrome.

    Cannavo, Claudia / Cleverley, Karen / Maduro, Cheryl / Mumford, Paige / Moulding, Dale / Fisher, Elizabeth M C / Wiseman, Frances K

    PloS one

    2022  Volume 17, Issue 5, Page(s) e0262558

    Abstract: 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-β plaques. Amyloid-β is a product of the processing of the amyloid precursor ... ...

    Abstract 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-β plaques. Amyloid-β 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-β 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.
    MeSH term(s) Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Biology ; Down Syndrome/genetics ; Down Syndrome/metabolism ; Endosomes/metabolism ; Fibroblasts/metabolism ; Mice ; Plaque, Amyloid/metabolism
    Chemical Substances Amyloid beta-Peptides ; Amyloid beta-Protein Precursor
    Language English
    Publishing date 2022-05-11
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0262558
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Using mouse models to understand Alzheimer's disease mechanisms in the context of trisomy of chromosome 21.

    Cannavo, Claudia / Tosh, Justin / Fisher, Elizabeth M C / Wiseman, Frances K

    Progress in brain research

    2019  Volume 251, Page(s) 181–208

    Abstract: People who have Down syndrome are at significantly elevated risk of developing early onset Alzheimer's disease that causes dementia (AD-DS). Here we review recent progress in modeling the development of AD-DS in mouse models. These studies provide ... ...

    Abstract People who have Down syndrome are at significantly elevated risk of developing early onset Alzheimer's disease that causes dementia (AD-DS). Here we review recent progress in modeling the development of AD-DS in mouse models. These studies provide insight into mechanisms underlying Alzheimer's disease and generate new clinical research questions. In addition, they suggest potential new targets for disease prevention therapies.
    MeSH term(s) Alzheimer Disease/drug therapy ; Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Animals ; Disease Models, Animal ; Down Syndrome/drug therapy ; Down Syndrome/genetics ; Down Syndrome/metabolism ; Down Syndrome/pathology ; Mice
    Language English
    Publishing date 2019-11-29
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ISSN 1875-7855 ; 0079-6123
    ISSN (online) 1875-7855
    ISSN 0079-6123
    DOI 10.1016/bs.pbr.2019.10.004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Cathepsin B abundance, activity and microglial localisation in Alzheimer's disease-Down syndrome and early onset Alzheimer's disease; the role of elevated cystatin B.

    Wu, Yixing / Mumford, Paige / Noy, Suzanna / Cleverley, Karen / Mrzyglod, Alicja / Luo, Dinghao / van Dalen, Floris / Verdoes, Martijn / Fisher, Elizabeth M C / Wiseman, Frances K

    Acta neuropathologica communications

    2023  Volume 11, Issue 1, Page(s) 132

    Abstract: 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 ... ...

    Abstract 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
    MeSH term(s) Humans ; Mice ; Animals ; Down Syndrome/pathology ; Alzheimer Disease/pathology ; Cystatin B/genetics ; Cathepsin B ; Microglia/metabolism
    Chemical Substances Cystatin B (88844-95-5) ; Cathepsin B (EC 3.4.22.1)
    Language English
    Publishing date 2023-08-14
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2715589-4
    ISSN 2051-5960 ; 2051-5960
    ISSN (online) 2051-5960
    ISSN 2051-5960
    DOI 10.1186/s40478-023-01632-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Endosomal structure and APP biology are not altered in a preclinical mouse cellular model of Down syndrome

    Claudia Cannavo / Karen Cleverley / Cheryl Maduro / Paige Mumford / Dale Moulding / Elizabeth M. C. Fisher / Frances K. Wiseman

    PLoS ONE, Vol 17, Iss

    2022  Volume 5

    Abstract: 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-β plaques. Amyloid-β is a product of the processing of the amyloid precursor ... ...

    Abstract 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-β plaques. Amyloid-β 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-β 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.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2022-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Endosomal structure and APP biology are not altered in a preclinical mouse cellular model of Down syndrome.

    Claudia Cannavo / Karen Cleverley / Cheryl Maduro / Paige Mumford / Dale Moulding / Elizabeth M C Fisher / Frances K Wiseman

    PLoS ONE, Vol 17, Iss 5, p e

    2022  Volume 0262558

    Abstract: 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-β plaques. Amyloid-β is a product of the processing of the amyloid precursor ... ...

    Abstract 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-β plaques. Amyloid-β 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-β 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.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2022-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Cognitive enhancement therapy for a model of Down syndrome.

    Wiseman, Frances K

    Science translational medicine

    2009  Volume 1, Issue 7, Page(s) 7ps9

    Abstract: Down syndrome is a complex condition that results from having a third copy of human chromosome 21. People with the syndrome experience problems with learning and memory that affect many aspects of their lives. In this issue of Science Translational ... ...

    Abstract Down syndrome is a complex condition that results from having a third copy of human chromosome 21. People with the syndrome experience problems with learning and memory that affect many aspects of their lives. In this issue of Science Translational Medicine, Salehi et al. report on successful drug treatment of learning deficits in an animal model of Down syndrome. This study highlights the function of the norepinephrine-ergic system in Down syndrome and suggests possible treatment options for people with Down syndrome.
    MeSH term(s) Animals ; Cognition ; Disease Models, Animal ; Down Syndrome/physiopathology ; Down Syndrome/psychology ; Humans ; Mice ; Models, Theoretical ; Norepinephrine/physiology ; Signal Transduction
    Chemical Substances Norepinephrine (X4W3ENH1CV)
    Language English
    Publishing date 2009-11-18
    Publishing country United States
    Document type Comment ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2518854-9
    ISSN 1946-6242 ; 1946-6234
    ISSN (online) 1946-6242
    ISSN 1946-6234
    DOI 10.1126/scitranslmed.3000449
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: The effects of Cstb duplication on APP/amyloid-β pathology and cathepsin B activity in a mouse model.

    Wu, Yixing / Whittaker, Heather T / Noy, Suzanna / Cleverley, Karen / Brault, Veronique / Herault, Yann / Fisher, Elizabeth M C / Wiseman, Frances K

    PloS one

    2021  Volume 16, Issue 7, Page(s) e0242236

    Abstract: 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, ... ...

    Abstract 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-β 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-β pathology in a transgenic mouse model of amyloid-β deposition. Multiple lines of evidence indicate that cysteine cathepsin activity influences APP cleavage and amyloid-β 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-β 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-β plaques or the levels of soluble or insoluble amyloid-β42, amyloid-β40, or amyloid-β38 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.
    MeSH term(s) Aging ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/genetics ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Cathepsin B/metabolism ; Cerebral Cortex/enzymology ; Cerebral Cortex/metabolism ; Cystatin B/genetics ; Cystatin B/metabolism ; Disease Models, Animal ; Female ; Gene Duplication ; Hippocampus/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic
    Chemical Substances Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Cystatin B (88844-95-5) ; Cathepsin B (EC 3.4.22.1)
    Language English
    Publishing date 2021-07-22
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0242236
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Publisher Correction: Genetic dissection of down syndrome‑associated alterations in APP/amyloid‑β biology using mouse models.

    Tosh, Justin L / Rhymes, Elena R / Mumford, Paige / Whittaker, Heather T / Pulford, Laura J / Noy, Sue J / Cleverley, Karen / Walker, Matthew C / Tybulewicz, Victor L J / Wykes, Rob C / Fisher, Elizabeth M C / Wiseman, Frances K

    Scientific reports

    2021  Volume 11, Issue 1, Page(s) 14966

    Language English
    Publishing date 2021-07-16
    Publishing country England
    Document type Published Erratum
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-021-94313-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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