Transgenic
            <i>Drosophila</i>
            expressing human amyloid precursor protein show γ-secretase activity and a blistered-wing phenotype

Fossgreen, Anke; Brückner, Bodo; Czech, Christian; Masters, Colin L.; Beyreuther, Konrad; Paro, Renato

doi:10.1073/pnas.95.23.13703

Cited by 142 publications

(109 citation statements)

References 38 publications

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“…39 A number of APP Drosophila models has also been developed, and it has been demonstrated that Drosophila can produce Ab peptide and develop neurodegeneration and memory decline. 40,41 Moreover, Drosophila overexpressing APP and BACE have been used for drug testing. Administration of either BACE inhibitor or c-secretase inhibitor increased survival rates of this Drosophila model.…”

Section: Introductionmentioning

confidence: 99%

Animal models of neurodegenerative diseases

Ribeiro

Camargos

Souza

et al. 2013

Rev. Bras. Psiquiatr.

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Section: Introductionmentioning

confidence: 99%

Animal models of neurodegenerative diseases

Ribeiro

Camargos

Souza

et al. 2013

Rev. Bras. Psiquiatr.

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“…In Drosophila, all components involved in the protein complex responsible for ␥-secretase activity are highly conserved (17), whereas ␤-secretase activity is absent or very low (18). An APP-like protein (APPL) is also present in flies, although the A␤ domain is not conserved.…”

mentioning

confidence: 99%

Dissecting the pathological effects of human Aβ40 and Aβ42 in Drosophila : A potential model for Alzheimer's disease

Iijima

Liu

Chiang

et al. 2004

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

439

441

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Accumulation of amyloid-␤ (A␤) peptides in the brain has been suggested to be the primary event in sequential progression of Alzheimer's disease (AD). Here, we use Drosophila to examine whether expression of either the human A␤40 or A␤42 peptide in the Drosophila brain can induce pathological phenotypes resembling AD. The expression of A␤42 led to the formation of diffused amyloid deposits, age-dependent learning defects, and extensive neurodegeneration. In contrast, expression of A␤40 caused only age-dependent learning defects but did not lead to the formation of amyloid deposits or neurodegeneration. These results strongly suggest that accumulation of A␤42 in the brain is sufficient to cause behavioral deficits and neurodegeneration. Moreover, Drosophila may serve as a model for facilitating the understanding of molecular mechanisms underlying A␤ toxicity and the discovery of novel therapeutic targets for AD. A lzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by progressive decline in memory accompanied by histological changes, including neuronal loss and the formation of neurofibrillary tangles (NFTs) and senile plaques (1). The accumulation of amyloid-␤ (A␤)42 peptide, the major component of senile plaques, has been hypothesized to be the primary event in AD pathogenesis (2, 3). The strongest support for the A␤ hypothesis comes from genetic analyses of familial AD (FAD); most FAD mutations identified in A␤ precursor protein (APP), Presenilin1 (PS1) and Presenilin2 (PS2) genes appear to cause excessive accumulation of A␤42 (4). Secretion of A␤ peptides is a result of sequential cleavage of APP by ␤-secretase, a type I transmembrane glycosylated aspartyl protease, and ␥-secretase, a large protein complex that includes at least four proteins, Presenilins (PS1 or PS2), Nicastrin, Aph-1, and Pen-2 (for review, see ref. 5). The heterogeneity of ␥-secretase cleavage gives rise to a series of A␤ peptides, including the major species A␤40 and a smaller amount of A␤42.To study AD pathogenesis in vivo, a number of AD mouse models have been established and have successfully recapitulated AD-like phenotypes, including abundant amyloid deposits, astroglial activation, synaptic loss and dysfunction, behavioral abnormalities, and neurodegeneration (6-15). In addition to these mouse models, the model systems that allow highthroughput genetic screening will facilitate the discovery of genes involved in AD pathogenesis. Furthermore, one of the intriguing issues that have not been elucidated in these transgenic mice is the pathological roles of each specific A␤ species (i.e., A␤40 and A␤42), because currently available mouse models mainly rely on overexpression of APP.We use a Drosophila model (16) to compare the specific pathological roles of A␤40 and A␤42. In Drosophila, all components involved in the protein complex responsible for ␥-secretase activity are highly conserved (17), whereas ␤-secretase activity is absent or very low (18). An APP-like protein (APPL) is also present in flies, althou...

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“…For example, most triple knock-out mice developed cortical dysplasias, a condition that could result from defects in the adhesion of migrating neurons to extracellular matrix (4). Overexpression of apl-1 in the worm caused organ detachment (7), and transgenic flies expressing human APP developed a blistered-wing phenotype (12). Furthermore, in cell cultures, APP appears to concentrate to sites of adhesion (13)(14)(15).…”

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confidence: 99%

Structural Characterization of the E2 Domain of APL-1, a Caenorhabditis elegans Homolog of Human Amyloid Precursor Protein, and Its Heparin Binding Site

Hoopes

Liu

et al. 2010

Journal of Biological Chemistry

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The amyloid ␤-peptide deposit found in the brain tissue of patients with Alzheimer disease is derived from a large heparinbinding protein precursor APP. The biological function of APP and its homologs is not precisely known. Here we report the x-ray structure of the E2 domain of APL-1, an APP homolog in Caenorhabditis elegans, and compare it to the human APP structure. We also describe the structure of APL-1 E2 in complex with sucrose octasulfate, a highly negatively charged disaccharide, which reveals an unexpected binding pocket between the two halves of E2. Based on the crystal structure, we are able to map, using site-directed mutagenesis, a surface groove on E2 to which heparin may bind. Our biochemical data also indicate that the affinity of E2 for heparin is influenced by pH: at pH 5, the binding appears to be much stronger than that at neutral pH. This property is likely caused by histidine residues in the vicinity of the mapped heparin binding site and could be important for the proposed adhesive function of APL-1. Amyloid precursor protein (APP)3 belongs to a gene family that in mammals includes two additional members, APLP1 and APLP2 (1-3). This gene family is important for viability because mice lacking all three members die shortly after birth (4). The function of APP and APP-like proteins and why their loss causes death are, however, not clear. Rare mutations in the human APP gene are also known to cause familial Alzheimer disease (for a review, see Ref. 5). The nematode Caenorhabditis elegans has a single APP-related gene, apl-1 (6). Inactivation of apl-1 prevents proper molting, a process that allows the worm to shed old cuticles between larval stages, and causes several other morphological defects (7).APP and APP-related proteins are type I membrane proteins. The majority of the full-length protein resides on the extracellular side of the membrane (Fig. 1A), and contains two conserved domains (E1, E2). E1 and E2 are retained in soluble forms of the protein, which are proteolytically released from the membrane by secretases. So far neither the primary sequence nor the three-dimensional structure of these two conserved domains has revealed any homology that would allow a convincing assignment of biological function to APP (8 -11). There are, however, a number of experimental observations suggesting that the APP family of proteins might play a role in regulating cell adhesion. For example, most triple knock-out mice developed cortical dysplasias, a condition that could result from defects in the adhesion of migrating neurons to extracellular matrix (4). Overexpression of apl-1 in the worm caused organ detachment (7), and transgenic flies expressing human APP developed a blistered-wing phenotype (12). Furthermore, in cell cultures, APP appears to concentrate to sites of adhesion (13-15).The structure of human E2/CAPPD has been solved by x-ray crystallography and NMR (10,11,22). In the x-ray structure, which contains the entire E2 region, the molecule forms a headto-tail dimer (10). This observation ...

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Transgenic Drosophila expressing human amyloid precursor protein show γ-secretase activity and a blistered-wing phenotype

Cited by 142 publications

References 38 publications

Animal models of neurodegenerative diseases

Animal models of neurodegenerative diseases

Dissecting the pathological effects of human Aβ40 and Aβ42 in Drosophila : A potential model for Alzheimer's disease

Structural Characterization of the E2 Domain of APL-1, a Caenorhabditis elegans Homolog of Human Amyloid Precursor Protein, and Its Heparin Binding Site

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