Modeling the complex pathology of Alzheimer's disease in Drosophila

Fernández-Fúnez, Pedro; Mena, Lorena de; Rincón-Limas, Diego E.

doi:10.1016/j.expneurol.2015.05.013

Cited by 62 publications

(48 citation statements)

References 164 publications

(190 reference statements)

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“…Overall, the sequence homology in genes of interest in AD is minimal between invertebrates and humans and these invertebrate orthologues often lack regions of these genes that are important in AD pathophysiology. The most notable example is the lack of Aβ in Drosophila and C. Elegans [1, 38]. Therefore, invertebrates cannot be considered to model AD without genetic manipulation to express human transgenes of APP, Aβ and/or tau.…”

Section: Drosophila C Elegans and Zebrafish As Ad Modelsmentioning

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: Drosophila C Elegans and Zebrafish As Ad Modelsmentioning

confidence: 99%

Alzheimer’s disease: experimental models and reality

2016

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“…Drosophila has played an instrumental role in the identification of genetic and molecular mechanisms mediating the neurotoxicity of misfolded amyloids, with particular attention to AD (23,24). A key advantage of Drosophila models is the ability to efficiently test candidate genes.…”

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confidence: 99%

Holdase activity of secreted Hsp70 masks amyloid-β42 neurotoxicity in Drosophila

Fernández-Fúnez

Sanchez-Garcia

Mena

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Alzheimer’s disease (AD) is the most prevalent of a large group of related proteinopathies for which there is currently no cure. Here, we used Drosophila to explore a strategy to block Aβ42 neurotoxicity through engineering of the Heat shock protein 70 (Hsp70), a chaperone that has demonstrated neuroprotective activity against several intracellular amyloids. To target its protective activity against extracellular Aβ42, we added a signal peptide to Hsp70. This secreted form of Hsp70 (secHsp70) suppresses Aβ42 neurotoxicity in adult eyes, reduces cell death, protects the structural integrity of adult neurons, alleviates locomotor dysfunction, and extends lifespan. SecHsp70 binding to Aβ42 through its holdase domain is neuroprotective, but its ATPase activity is not required in the extracellular space. Thus, the holdase activity of secHsp70 masks Aβ42 neurotoxicity by promoting the accumulation of nontoxic aggregates. Combined with other approaches, this strategy may contribute to reduce the burden of AD and other extracellular proteinopathies.

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“…Postmortem samples of brain or eye tissues can be used only to observe the end results of neurodegenerative processes, which do not necessarily reflect the mechanisms responsible for disease development. Thus, much of research has been traditionally based on the use of animal models, to both improve our understanding of the pathophysiological mechanisms of the disease and to test novel therapeutic approaches [8–12]. We believe that the use of accelerated-senescence OXYS rats, which spontaneously develop both AMD-like retinopathy and the key signs of Alzheimer’s disease, represent unique opportunities for research in this field.…”

Section: Introductionmentioning

confidence: 99%

Genes of susceptibility to early neurodegenerative changes in the rat retina and brain: analysis by means of congenic strains

et al. 2016

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BackgroundThere has been considerable interest in discovery of the genetic architecture of complex traits, particularly age-related neurodegenerative disorders. To predict disease risk and to understand its genetic basis in humans, it is necessary to study animal models. Our previous research on the accelerated-senescence OXYS strain has revealed two quantitative trait loci (QTLs) on rat chromosome 1 that are associated with early cataract and/or retinopathy as well as with behavioral abnormalities. Each locus was partially mapped within the introgressed segments in a certain congenic strain: WAG/OXYS-1.1 or WAG/OXYS-1.2. Retinal transcriptome profiling of 20-day-old congenic and OXYS rats by high-throughput RNA sequencing uncovered relevant candidate genes and pathways. Nonetheless, the question remained open whether the same genetic components simultaneously have effects on various manifestations of the accelerated-senescence phenotype in OXYS rats. The present study was designed to analyze the genes of susceptibility to early neurodegenerative processes taking place in the OXYS rat retina and brain and to assess their potential functional clustering. The study was based on the findings from recent publications (including mapping of quantitative trait loci) and on comparative phenotyping of congenic rat strains.ResultsThe backcrossing of Wistar Albino Glaxo (WAG) and OXYS strains to generate the congenics resulted in two congenic strains with high susceptibility to cataract and retinopathy but with no obvious signs of Alzheimer’s disease-like brain pathology that are specific for OXYS rats. Thus, the genes of susceptibility to brain neurodegeneration were not introgressed into the congenic strains or there is a strong effect of the genetic background on the disease phenotype. Moreover, the progression of retinopathy with age was relatively less severe in the WAG background compared to the OXYS background. A comparative analysis of previously defined QTLs and congenic segments led to identification of candidate genes with a suspected effect on brain neurodegeneration including the genes showing differential expression in the congenic strains.ConclusionOverall, our findings suggest that the cause of the cataract and the cause of retinopathy phenotypes in OXYS rats may be genetically linked to each other within the introgressed segments in the WAG/OXYS-1.1 and/or WAG/OXYS-1.2 congenic strains.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0461-7) contains supplementary material, which is available to authorized users.

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Modeling the complex pathology of Alzheimer's disease in Drosophila

Cited by 62 publications

References 164 publications

Alzheimer’s disease: experimental models and reality

Alzheimer’s disease: experimental models and reality

Holdase activity of secreted Hsp70 masks amyloid-β42 neurotoxicity in Drosophila

Genes of susceptibility to early neurodegenerative changes in the rat retina and brain: analysis by means of congenic strains

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