Endocytic pathways mediating oligomeric Aβ42 neurotoxicity

Yu, Chunjiang; Nwabuisi-Heath, Evelyn; Laxton, Kevin; LaDu, Mary Jo

doi:10.1186/1750-1326-5-19

Cited by 56 publications

(66 citation statements)

References 91 publications

(73 reference statements)

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“…A recent study showed that, in mice with a toxin-induced compromise of the blood-brain barrier, fluorescently labeled A␤ that is injected into the tail vein can accumulate intracellularly in pyramidal neurons in the cerebral cortex [110]. The results presented by the authors provide direct evidence that neurons can take up extracellular A␤, one of mechanisms that has been proposed is the endocytocis of A␤ oligomers [111].…”

Section: Intracellular A␤ Oligomer Toxicitymentioning

confidence: 89%

Molecular Mechanisms of Amyloid Oligomers Toxicity

Kayed

Lasagna‐Reeves

2012

JAD

326

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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Section: Intracellular A␤ Oligomer Toxicitymentioning

confidence: 89%

Molecular Mechanisms of Amyloid Oligomers Toxicity

Kayed

Lasagna‐Reeves

2012

JAD

326

283

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“…For example, inactivated RhoA can reduce the uptake of oligomeric Aβ42 in N2A cells as part of the mechanism to defend cells from oligomeric Aβ42-induced neurotoxicity [73]. Activated RhoA inhibits transferrin-receptor-mediated endocytosis in Hela cells [57], the muscarinic acetylcholine receptors trafficking to the plasma membrane in HEK293 cells [74] and the uptake of fetuin-A in bovine vascular smooth muscle cells [75].…”

Section: Role Of Rho Gtpases In Vesicular Transportmentioning

confidence: 99%

Roles of Rho GTPases in Intracellular Transport and Cellular Transformation

Chi

Wang

Huang

et al. 2013

IJMS

103

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Rho family GTPases belong to the Ras GTPase superfamily and transduce intracellular signals known to regulate a variety of cellular processes, including cell polarity, morphogenesis, migration, apoptosis, vesicle trafficking, viral transport and cellular transformation. The three best-characterized Rho family members are Cdc42, RhoA and Rac1. Cdc42 regulates endocytosis, the transport between the endoplasmic reticulum and Golgi apparatus, post-Golgi transport and exocytosis. Cdc42 influences trafficking through interaction with Wiskott-Aldrich syndrome protein (N-WASP) and the Arp2/3 complex, leading to changes in actin dynamics. Rac1 mediates endocytic and exocytic vesicle trafficking by interaction with its effectors, PI3kinase, synaptojanin 2, IQGAP1 and phospholipase D1. RhoA participates in the regulation of endocytosis through controlling its downstream target, Rho kinase. Interestingly, these GTPases play important roles at different stages of viral protein and genome transport in infected host cells. Importantly, dysregulation of Cdc42, Rac1 and RhoA leads to numerous disorders, including malignant transformation. In some cases, hyperactivation of Rho GTPases is required for cellular transformation. In this article, we review a number of findings related to Rho GTPase function in intracellular transport and cellular transformation.

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“…The clathrin coat then depolymerizes followed by delivery of the cargo to early endosomes and then to late endosomes/lysosomes for degradation or to recycling endosomes for recycling of the receptor back to the PM [45]. Although the evidence for human amylin internalization pathways, particularly in pancreatic cells is scarce [4], [49], [50], many studies have revealed the involvement of a multitude of endocytotic pathways in uptake of other amyloid peptides in a variety of cell types and tissues [47], [51]–[54]. For example, low density lipoprotein 1 receptor has been shown to internalize soluble forms of β-amyloid complexed with apolipoprotein E mainly through the CME in neuroblastoma and neuronal cell lines [52].…”

Section: Introductionmentioning

confidence: 99%

Distinct Internalization Pathways of Human Amylin Monomers and Its Cytotoxic Oligomers in Pancreatic Cells

Trikha

Jeremić

2013

PLoS ONE

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Toxic human amylin oligomers and aggregates are implicated in the pathogenesis of type 2 diabetes mellitus (TTDM). Although recent studies have shown that pancreatic cells can recycle amylin monomers and toxic oligomers, the exact uptake mechanism and trafficking routes of these molecular forms and their significance for amylin toxicity are yet to be determined. Using pancreatic rat insulinoma (RIN-m5F) beta (β)-cells and human islets as model systems we show that monomers and oligomers cross the plasma membrane (PM) through both endocytotic and non-endocytotic (translocation) mechanisms, the predominance of which is dependent on amylin concentrations and incubation times. At low (≤100 nM) concentrations, internalization of amylin monomers in pancreatic cells is completely blocked by the selective amylin-receptor (AM-R) antagonist, AC-187, indicating an AM-R dependent mechanism. In contrast at cytotoxic (µM) concentrations monomers initially (1 hour) enter pancreatic cells by two distinct mechanisms: translocation and macropinocytosis. However, during the late stage (24 hours) monomers internalize by a clathrin-dependent but AM-R and macropinocytotic independent pathway. Like monomers a small fraction of the oligomers initially enter cells by a non-endocytotic mechanism. In contrast a majority of the oligomers at both early (1 hour) and late times (24 hours) traffic with a fluid-phase marker, dextran, to the same endocytotic compartments, the uptake of which is blocked by potent macropinocytotic inhibitors. This led to a significant increase in extra-cellular PM accumulation, in turn potentiating amylin toxicity in pancreatic cells. Our studies suggest that macropinocytosis is a major but not the only clearance mechanism for both amylin’s molecular forms, thereby serving a cyto-protective role in these cells.

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Endocytic pathways mediating oligomeric Aβ42 neurotoxicity

Cited by 56 publications

References 91 publications

Molecular Mechanisms of Amyloid Oligomers Toxicity

Molecular Mechanisms of Amyloid Oligomers Toxicity

Roles of Rho GTPases in Intracellular Transport and Cellular Transformation

Distinct Internalization Pathways of Human Amylin Monomers and Its Cytotoxic Oligomers in Pancreatic Cells

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