β-Amyloid Accumulation Impairs Multivesicular Body Sorting by Inhibiting the Ubiquitin-Proteasome System

Almeida, Cláudia G.; Takahashi, Riku; Gouras, Gunnar K.

doi:10.1523/jneurosci.5078-05.2006

Cited by 289 publications

(243 citation statements)

References 57 publications

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“…In human patients, it is well studied that an increased level of egfr expression is closely related to tumorigenesis (40); however, the relationship between the EGFR pathway and AD is not clear. Previous reports showed that presenilin and Aβ could regulate the expression and metabolism of EGFR, which suggested the involvement of EGFR in the AD process (15,41,42). In our study, enhanced EGFR activity likely resulted from Aβ oligomers-dependent activation, possibly through direct binding.…”

Section: Discussionsupporting

confidence: 62%

“…They can be removed through activities of neprilysin, insulin-degradation enzyme, and possibly other mechanisms (5)(6)(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)(14)(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.…”

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confidence: 99%

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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.

158

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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Section: Discussionsupporting

confidence: 62%

mentioning

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.

158

141

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“…Specifically, it reconciles the known extracellular deposition of terminal amyloid plaques in AD patients or AD mouse models (15, 23) with numerous observations from AD patients (33), AD mouse models (34) and Aβ-transgenic Drosophila melanogaster flies (35) showing that Aβ species may also accumulate inside the cell, including MVBs (16,36,37), lysosomes or other vesicular compartments (38)(39)(40). The present observation of an intracellular route of amyloid plaque formation is consistent with observations that extracellular amyloid plaques typically contain a spectrum of proteins that are originally intracellular.…”

Section: Discussionmentioning

confidence: 52%

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.

280

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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“…Almeida et al demonstrated that in A␤PP mutant transgenic mice and in human AD brain, progressive intraneuronal accumulation of A␤ occurs, especially in multivesicular bodies (MVBs) [121]. The authors provided evidence that A␤ accumulation in neurons inhibits the activities of the proteasome and deubiquitinating enzymes.…”

Section: Intracellular A␤ Oligomer Toxicitymentioning

confidence: 99%

Molecular Mechanisms of Amyloid Oligomers Toxicity

Kayed

Lasagna‐Reeves

2012

JAD

323

283

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Abstract. Amyloid oligomers have emerged as the most toxic species of amyloid-␤ (A␤). This hypothesis might explain the lack of correlation between amyloid plaques and memory impairment or cellular dysfunction. However, despite the numerous published research articles supporting the critical role A␤ oligomers in synaptic dysfunction and cell death, the exact definition and mechanism of amyloid oligomers formation and toxicity still elusive. Here we review the evidence supporting the many molecular mechanisms proposed for amyloid oligomers toxicity and suggest that the complexity and dynamic nature of amyloid oligomers may be responsible for the discrepancy among these mechanisms and the proposed cellular targets for amyloid oligomers.

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β-Amyloid Accumulation Impairs Multivesicular Body Sorting by Inhibiting the Ubiquitin-Proteasome System

Cited by 289 publications

References 57 publications

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

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

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

Molecular Mechanisms of Amyloid Oligomers Toxicity

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