Aβ42 Mutants with Different Aggregation Profiles Induce Distinct Pathologies in Drosophila

Iijima, Koichi; Chiang, Hsueh Cheng; Hearn, Stephen; Hakker, Inessa; Gatt, Anthony; Shenton, Christopher; Granger, Linda; Leung, Amy; Iijima-Ando, Kanae; Zhong, Yi

doi:10.1371/journal.pone.0001703

Cited by 157 publications

(209 citation statements)

References 43 publications

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“…Support for the notion that Aβ-internalization by nonneuronal cells represents a possible pathway toward Aβ aggregation comes also from observations that neuronal expression of Aβ in transgenic animals produces intravesicular Aβ aggregates within neighboring glia cells (59). Evidently, these glia cells must have internalized the Aβ peptide that was secreted initially from adjacent neuronal cells.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of amyloid plaque formation suggests an intracellular basis of Aβ pathogenicity

Friedrich

Tepper²,

Rönicke³

et al. 2010

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

284

220

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The formation of extracellular amyloid plaques is a common patho-biochemical event underlying several debilitating human conditions, including Alzheimer’s disease (AD). Considerable evidence implies that AD damage arises primarily from small oligomeric amyloid forms of Aβ peptide, but the precise mechanism of pathogenicity remains to be established. Using a cell culture system that reproducibly leads to the formation of Alzheimer’s Aβ amyloid plaques, we show here that the formation of a single amyloid plaque represents a template-dependent process that critically involves the presence of endocytosis- or phagocytosis-competent cells. Internalized Aβ peptide becomes sorted to multivesicular bodies where fibrils grow out, thus penetrating the vesicular membrane. Upon plaque formation, cells undergo cell death and intracellular amyloid structures become released into the extracellular space. These data imply a mechanism where the pathogenic activity of Aβ is attributed, at least in part, to intracellular aggregates.

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Section: Discussionmentioning

confidence: 99%

Mechanism of amyloid plaque formation suggests an intracellular basis of Aβ pathogenicity

Friedrich

Tepper²,

Rönicke³

et al. 2010

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

284

220

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“…Human wild-type Aβ42 transgenic flies (UAS-Aβ42) used in this study have been previously described (21). UAS-InR wt and UAS-EGFR wt were obtained from the Bloomington Drosophila Stock Center.…”

Section: Methodsmentioning

confidence: 99%

“…Aβ-induced memory loss is observed across a wide range of organisms including Drosophila, mice, and humans, suggesting a conserved underlying molecular mechanism (18,19). In Drosophila, expression of a secretory form of human Aβ42 in the brain recapitulates AD-like features, such as age-dependent accumulation of Aβ deposits, memory loss, and late-onset severe neurodegeneration (20,21). Our earlier work reveals a role of PI3-kinase in Aβ42-induced alteration in long-term depression and memory loss (17).…”

Section: Ameliorating Aβ42-induced Memory Loss By Inhibition Of Egfrs Inmentioning

confidence: 99%

Epidermal growth factor receptor is a preferred target for treating Amyloid-β–induced memory loss

Wang

Chiang

et al. 2012

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

Self Cite

162

141

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Current understanding of amyloid-β (Aβ) metabolism and toxicity provides an extensive list of potential targets for developing drugs for treating Alzheimer's disease. We took two independent approaches, including synaptic-plasticity-based analysis and behavioral screening of synthetic compounds, for identifying single compounds that are capable of rescuing the Aβ-induced memory loss in both transgenic fruit fly and transgenic mouse models. Two clinically available drugs and three synthetic compounds not only showed positive effects in behavioral tests but also antagonized the Aβ oligomers-induced activation of the epidermal growth factor receptor (EGFR). Such surprising converging outcomes from two parallel approaches lead us to conclude that EGFR is a preferred target for treating Aβ-induced memory loss.A myloid-β (Aβ) oligomers-induced memory loss is thought to be a hallmark of Alzheimer's disease (AD) progression (1-3). Aβ peptides are cleaved from a membrane protein APP via β-and γ-secretases' activities (4). They can be removed through activities of neprilysin, insulin-degradation enzyme, and possibly other mechanisms (5-7). Aβ is also able to bind with a large array of target proteins, such as EphB2, TNF-R1, RAGE1, and NMDA receptor and prion (8)(9)(10)(11)(12) to exert a wide range of effects, including synaptic transmission, protein transportation, mitochondrial functions, and others (13-15). Thus, there are a large number of potential targets for developing AD treatment based on the Aβ hypothesis, for example, the mechanisms either reducing the production of Aβ peptides or enhancing the degradation process. It remains, however, an open question as to whether some of these targets are, at the organism level, better suited for drug development than others. One important reason is that manipulating activities of such production and degradation enzymes may affect many other physiological proteins. Thus, reported failures in a number of Aβ-based drug efforts (16) stress the necessity of identifying such preferred targets.To evaluate the possibility of finding preferred targets, we looked for overlapping and converging effects of identified targets with multiple independent approaches. First, following the direction of a synaptic-plasticity-based, mechanism-guided study, we continued to work on the signal transduction pathway of PI3-kinase that has been shown to mediate an Aβ-induced change in long-term synaptic depression as well as the Aβ-induced memory loss in Aβ42-expressing Drosophila, which recapitulates several ADlike symptoms (17). These efforts led us to find Aβ42 oligomersinduced activation of the epidermal growth factor receptor (EGFR) and the rescue of Aβ-induced memory loss in transgenic Drosophila and APP/PS1 double transgenic mouse models through treatments with clinically available EGFR inhibitors. Second, we worked to identify single compounds capable of rescuing Aβ-induced memory loss through large-scale behavioral screening with Aβ42-expressing transgenic fruit flies, followed by a confirma...

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“…In other work, flies expressing wild-type А 42 and Arctic mutant А 42 (Glu22Gly) showed a decline in climbing behavior, increased intracellular А accumulation and diffuse plaques prior to signs of neurodegeneration [Crowther et al, 2005]. Late findings demonstrated that expression of the Arctic mutant significantly enhanced formation of А oligomers and А deposits, together with a decline of locomotor functions when compared with А -art (artificial mutation L17P) [Iijima et al, 2008]. It has been proposed that dysfunction and loss of synapses underlie in the basis of cognitive disturbances at AD [Hardy & Selkoe, 2002;Honer, 2003Sze et al, 1997Selkoe, 2002;Terry et al, 1991].…”

Section: Drosophila Models Of Alzheimer's Amyloidosismentioning

confidence: 91%

Modeling Amyloid Diseases in Fruit Fly Drosophila Melanogaster

Саранцева¹,

Schwarzman²

2011

Amyloidosis - Mechanisms and Prospects for Therapy

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Aβ42 Mutants with Different Aggregation Profiles Induce Distinct Pathologies in Drosophila

Cited by 157 publications

References 43 publications

Mechanism of amyloid plaque formation suggests an intracellular basis of Aβ pathogenicity

Mechanism of amyloid plaque formation suggests an intracellular basis of Aβ pathogenicity

Epidermal growth factor receptor is a preferred target for treating Amyloid-β–induced memory loss

Modeling Amyloid Diseases in Fruit Fly Drosophila Melanogaster

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