Using the zebrafish model for Alzheimerâ€™s disease research

Newman, Morgan; Ebrahimie, Esmaeil; Lardelli, Michael

doi:10.3389/fgene.2014.00189

Cited by 111 publications

(67 citation statements)

References 110 publications

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“…To date, the vast majority of experimental models are animal models, almost exclusively consisting of transgenic mice that express human genes that result in the formation of amyloid plaques (by expression of human APP alone or in combination with human PSEN1 ) and neurofibrillary tangles (by expression of human MAPT )[14, 34, 117, 172, 173]. Other models have included invertebrate animals such as Drosophila melanogaster and Caenorhabditis elegans , as well as vertebrates such as zebrafish; however, given these models’ greater distance from human physiology they are less extensively used [13, 53, 104]. Since the development of the first transgenic mouse model with substantial amyloid plaque burden in 1995[42], there has been a proliferation of new transgenic models, each with a different phenotype of AD-associated pathology[34, 117, 173].…”

Section: Introductionmentioning

confidence: 99%

Alzheimer’s disease: experimental models and reality

2016

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Experimental models of Alzheimer’s disease (AD) are critical to gaining a better understanding of pathogenesis and to assess the potential of novel therapeutic approaches. The most commonly used experimental animal models are transgenic mice that overexpress human genes associated with familial AD (FAD) that result in the formation of amyloid plaques. However, AD is defined by the presence and interplay of both amyloid plaques and neurofibrillary tangle pathology. The track record of success in AD clinical trials thus far has been very poor. In part, this high failure rate has been related to the premature translation of highly successful results in animal models that mirror only limited aspects of AD pathology to humans. A greater understanding of the strengths and weakness of each of the various models and the use of more than one model to evaluate potential therapies would help enhance the success of therapy translation from preclinical studies to patients. In this review we summarize the pathological features and limitations of the major experimental models of AD including transgenic mice, transgenic rats, various physiological models of sporadic AD and in vitro human cell culture models.

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Section: Introductionmentioning

confidence: 99%

Alzheimer’s disease: experimental models and reality

2016

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“…To gain better insight into HMGA1 function and dysfunction, various animal models have been used. The zebrafish and its embryos are a highly manipulable vertebrate model for genetic studies due to a combination of advantageous features including easy embryo accessibility, large zygote size, relatively constant embryo size during its rapid development, short generation time and a well-characterised genome 32 . We have previously identified and studied a zebrafish co-orthologue of this gene, hmga1a 3 .…”

Section: Discussionmentioning

confidence: 99%

HMGA1 zebrafish co-orthologue hmga1b can modulate p53-dependent cellular responses but is unable to control the alternative splicing of psen1

Nik

Newman

Lumsden

et al. 2018

Preprint

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The HIGH MOBILITY GROUP AT-HOOK 1 (HMGA1) family of chromatin-binding proteins plays important roles in cellular responses to low oxygen. HMGA1 proteins regulate gene activity both in the nucleus and within mitochondria. They are expressed mainly during embryogenesis and their upregulation in cancerous cells indicates poor prognosis. The human HMGA1a isoform is upregulated under hypoxia via oxidative stress-dependent signalling and can then bind nascent transcripts of the familial Alzheimer's disease gene PSEN2 to regulate alternative splicing to produce the truncated PSEN2 protein isoform PS2V. Zebrafish where hmga1a expression is induced by hypoxia to control splicing of the psen1 gene to produce the PS2V-equivalent isoform PS1IV. Zebrafish possess a second gene with apparent HMGA1 orthology, hmga1b. Here we investigate the predicted structure of Hmga1b protein and demonstrate it to be co-orthologous to human HMGA1 and most similar in structure to human isoform HMGA1c. We show that forced over-expression of either hmga1a or hmga1b mRNA can suppress the action of the cytotoxin hydroxyurea in stimulating cell death and transcription of the genes mdm2 and cdkn1a that, in humans, are controlled by p53. Our experimental data support an important role for HMGA1 proteins in modulation of p53dependent responses and illuminate the evolutionary subfunctionalisation.

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“…elegans are now developed to study amyloidogenesis (reviewed in [101,102,103,104,105,106,107,108]). All of these models have specific limitations, the most important of which is the incomplete similarity with the human pathology development.…”

Section: Methods For Investigation Of the Amyloid Interactomementioning

confidence: 99%

Protein Co-Aggregation Related to Amyloids: Methods of Investigation, Diversity, and Classification

Bondarev

Antonets

Kajava

et al. 2018

IJMS

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Amyloids are unbranched protein fibrils with a characteristic spatial structure. Although the amyloids were first described as protein deposits that are associated with the diseases, today it is becoming clear that these protein fibrils play multiple biological roles that are essential for different organisms, from archaea and bacteria to humans. The appearance of amyloid, first of all, causes changes in the intracellular quantity of the corresponding soluble protein(s), and at the same time the aggregate can include other proteins due to different molecular mechanisms. The co-aggregation may have different consequences even though usually this process leads to the depletion of a functional protein that may be associated with different diseases. The protein co-aggregation that is related to functional amyloids may mediate important biological processes and change of protein functions. In this review, we survey the known examples of the amyloid-related co-aggregation of proteins, discuss their pathogenic and functional roles, and analyze methods of their studies from bacteria and yeast to mammals. Such analysis allow for us to propose the following co-aggregation classes: (i) titration: deposition of soluble proteins on the amyloids formed by their functional partners, with such interactions mediated by a specific binding site; (ii) sequestration: interaction of amyloids with certain proteins lacking a specific binding site; (iii) axial co-aggregation of different proteins within the same amyloid fibril; and, (iv) lateral co-aggregation of amyloid fibrils, each formed by different proteins.

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Using the zebrafish model for Alzheimerâ€™s disease research

Cited by 111 publications

References 110 publications

Alzheimer’s disease: experimental models and reality

Alzheimer’s disease: experimental models and reality

HMGA1 zebrafish co-orthologue hmga1b can modulate p53-dependent cellular responses but is unable to control the alternative splicing of psen1

Protein Co-Aggregation Related to Amyloids: Methods of Investigation, Diversity, and Classification

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