A Drosophila Model of Alzheimer's Disease

Crowther, Damian C.; Page, Richard; Chandraratna, Dhianjali; Lomas, David A.

doi:10.1016/s0076-6879(06)12015-7

Cited by 58 publications

(52 citation statements)

References 52 publications

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“…[35][36][37][38] (2) New ideas about protein aggregation, 10,28 including the finding that the ability to assemble into stable and highly organised structures (e.g. amyloid fibrils) is not an unusual feature exhibited by a small group of peptides and proteins with special sequence or structural properties, but rather a property shared by most, if not all, proteins; (3) The discovery that specific aspects of protein behaviour, including their aggregation propensities 21,23,39,40 and the cellular toxicity associated with the aggregation process, 24,41 can be predicted with a remarkable degree of accuracy from the knowledge of their amino acid sequences; (4) The realisation that a wide variety of techniques originally devised for applications in nanotechnology can be used to probe the nature of protein aggregation and assembly and of the structures that emerge; 30,[42][43][44] and (5) The development of powerful approaches using model organisms for probing the origins and progression of misfolding diseases by linking concepts and principles emerging from in vitro studies to in vivo phenomena such as neurodegeneration. 24 An analysis of these results, which span across a wide range of subjects from neuroscience to nanoscience, reveals that the ability to keep proteins in their soluble form is absolutely central for the maintenance of cell homeostasis.…”

Section: A Conceptual Framework For Understanding Protein Homeostasismentioning

confidence: 99%

“…24 The advantage of using Drosophila models for such studies is that the brevity of their lifecycle, the power of the associated genetic tools, and the ease with which a range of toxicity-related phenotypes may be measured allows us to quantify the links between the in vivo toxicity of protein aggregates and the fundamental chemical properties of peptides and proteins. 24,41,73,74 The results discussed above were obtained by developing a method for predicting the rate of formation of protofibrillar aggregates based on the physico-chemical properties of the amino acids comprising the sequences of the mutational variants of the Ab42 peptide that we have investigated. It is also remarkable that, despite the fact that the intrinsic aggregation propensities of typical protein sequences vary by at least five orders of magnitude, we have been able to achieve profound alterations in the pathogenic effects of Ab42 by increasing or decreasing its propensity to aggregate by less than 15%.…”

Section: Origins and Consequences Of Aggregation In Living Systemsmentioning

confidence: 99%

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Quantitative approaches to defining normal and aberrant protein homeostasis

Vendruscolo

2009

Faraday Discuss.

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Protein homeostasis refers to the ability of cells to generate and regulate the levels of their constituent proteins in terms of conformations, interactions, concentrations and cellular localisation. We discuss here an approach in which physico-chemical properties of proteins and their environments are used to understand the underlying principles governing this process, which is crucial in all living systems. By adopting the strategy of characterising the origins of specific diseases to inform us about normal biology, we are bringing together methods and concepts from chemistry, physics, engineering, genetics and medicine. In particular, we are using a combination of in vitro, in silico and in vivo approaches to study protein homeostasis through the analysis of the effects that result from its perturbation in a select group of specific proteins, from either amino acid mutations, or changes in concentration and solubility, or interactions with other molecules. By developing a coherent and quantitative description of such phenomena, we are finding that it is possible to shed new light on how the physical and chemical properties of the cellular components can provide an understanding of the normal and aberrant behaviour of living systems. Through such an approach it is possible to provide new insights into the origin and consequences of the failure to maintain homeostasis that is associated with neurodegenerative diseases, in particular, and the phenomenon of ageing, in general, and hence provide a framework for the rational design of therapeutic approaches.

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Section: A Conceptual Framework For Understanding Protein Homeostasismentioning

confidence: 99%

Section: Origins and Consequences Of Aggregation In Living Systemsmentioning

confidence: 99%

Quantitative approaches to defining normal and aberrant protein homeostasis

Vendruscolo

2009

Faraday Discuss.

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“…Aβ42 (oligomeric peptide; Chemicon International, Temecula, CA) and APP 96-110 (Ac-NWCKRGRKQCKTHPH-NH 2 , disulfide bond 3-10; AnaSpec, San Jose, CA) were used at concentrations from 0.1 to 1 µM or 0.5 to 10 µM, respectively, after preliminary studies established these ranges as appropriate to evaluations for threshold to maximal effects. These concentration ranges are similar to those shown to be required for Aβ42 toxicity in other lower organisms [20,22,30,33,51]. Lipophilic analogs of ACh (arachidonoyl dimethylaminoethanol, AA-DMAE), 5HT (arachidonoyl 5HT, AA-5-HT), and cannabinoids-vanilloids (arachidonoyl vanillylamine, AA-VAN) were evaluated at 10-40 µM, a concentration range found to be optimal in our previous experiments with a variety of neurotoxicants [12,15,19], including Aβ42 [13].…”

Section: Methodsmentioning

confidence: 55%

Amyloid precursor protein 96–110 and β-amyloid 1–42 elicit developmental anomalies in sea urchin embryos and larvae that are alleviated by neurotransmitter analogs for acetylcholine, serotonin and cannabinoids

Buznikov

Nikitina

Seidler

et al. 2008

Neurotoxicology and Teratology

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Amyloid precursor protein (APP) is overexpressed in the developing brain and portions of its extracellular domain, especially amino acid residues 96-110, play an important role in neurite Correspondence: Dr. T.A. Slotkin, Dept. of Pharmacology & Cancer Biology, Box 3813 DUMC, Duke University Medical Center, Durham, NC 27710-3813, Tel (919) 681 8015, Fax (919) 684 8197, e-mail: t.slotkin@duke.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. outgrowth and neural cell differentiation. In the current study, we evaluated the developmental abnormalities caused by administration of exogenous APP 96-110 in sea urchin embryos and larvae, which, like the developing mammalian brain, utilize acetylcholine and other neurotransmitters as morphogens; effects were compared to those of β-amyloid 1-42 (Aβ42), the neurotoxic APP fragment contained within neurodegenerative plaques in Alzheimer's Disease. Although both peptides elicited dysmorphogenesis, Aβ42 was far more potent; in addition, whereas Aβ42 produced abnormalities at developmental stages ranging from early cleavage divisions to the late pluteus, APP 96-110 effects were restricted to the intermediate, mid-blastula stage. For both agents, anomalies were prevented or reduced by addition of lipid-permeable analogs of acetylcholine, serotonin or cannabinoids; physostigmine, a carbamate-derived cholinesterase inhibitor, was also effective. In contrast, agents that act on NMDA receptors (memantine) or α-adrenergic receptors (nicergoline), and that are therapeutic in Alzheimer's Disease, were themselves embryotoxic, as was tacrine, a cholinesterase inhibitor from a different chemical class than physostigmine. Protection was also provided by agents acting downstream from receptor-mediated events: increasing cyclic AMP with caffeine or isobutylmethylxanthine, or administering the antioxidant, α-tocopherol, were all partially effective. Our findings reinforce a role for APP in development and point to specific interactions with neurotransmitter systems that act as morphogens in developing sea urchins as well as in the mammalian brain. NIH Public Access

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“…Although invertebrates may lack the neuronal and behavioral complexity of mammals, their use has been significant in directly investigating the molecular and cellular processes that underlie the disease process, and have allowed for rapid and clear observation of the phenotypes commonly associated with AD (Gotz et al, 2004;Link, 2005;Wu and Luo, 2005;Crowther et al, 2006). Importantly, these rapid disease models can potentially be exploited for use in highthroughput genetic and drug screening.…”

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confidence: 99%

Ascidians: an invertebrate chordate model to study Alzheimer’s disease pathogenesis

Virata

Zeller

2010

Disease Models &Amp; Mechanisms

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SUMMARY Here we present the ascidian Ciona intestinalis as an alternative invertebrate system to study Alzheimer’s disease (AD) pathogenesis. Through the use of AD animal models, researchers often attempt to reproduce various aspects of the disease, particularly the coordinated processing of the amyloid precursor protein (APP) by α-, β- and γ-secretases to generate amyloid beta (Aβ)-containing plaques. Recently, Drosophila and C. elegans AD models have been developed, exploiting the relative simplicity of these invertebrate systems, but they lack a functional Aβ sequence and a β-secretase ortholog, thus complicating efforts to examine APP processing in vivo. We propose that the ascidian is a more appropriate invertebrate AD model owing to their phylogenetic relationship with humans. This is supported by bioinformatic analyses, which indicate that the ascidian genome contains orthologs of all AD-relevant genes. We report that transgenic ascidian larvae can properly process human APP695 to generate Aβ peptides. Furthermore, Aβ can rapidly aggregate to form amyloid-like plaques, and plaque deposition is significantly increased in larvae expressing a human APP695 variant associated with familial Alzheimer’s disease. We also demonstrate that nervous system-specific Aβ expression alters normal larval behavior during attachment. Importantly, plaque formation and alterations in behavior are not only observed within 24 hours post-fertilization, but anti-amyloid drug treatment improves these AD-like pathologies. This ascidian model for AD provides a powerful and rapid system to study APP processing, Aβ plaque formation and behavioral alterations, and could aid in identifying factors that modulate amyloid deposition and the associated disruption of normal cellular function and behaviors.

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A Drosophila Model of Alzheimer's Disease

Cited by 58 publications

References 52 publications

Quantitative approaches to defining normal and aberrant protein homeostasis

Quantitative approaches to defining normal and aberrant protein homeostasis

Amyloid precursor protein 96–110 and β-amyloid 1–42 elicit developmental anomalies in sea urchin embryos and larvae that are alleviated by neurotransmitter analogs for acetylcholine, serotonin and cannabinoids

Ascidians: an invertebrate chordate model to study Alzheimer’s disease pathogenesis

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