Oligomeric Intermediates in Amyloid Formation: Structure Determination and Mechanisms of Toxicity

Fändrich, Marcus

doi:10.1016/j.jmb.2012.01.006

Cited by 310 publications

(326 citation statements)

References 152 publications

(247 reference statements)

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“…S3). The presence of fibrils is consistent with 5GDM analysis and the size values obtained for fibrils are in agreement with published studies [5,42,43].…”

Section: Evaluation Of the Four Fractions Of Ab 1-42 Aggregatessupporting

confidence: 93%

Simultaneous measurement of a range of particle sizes during Aβ1–42 fibrillogenesis quantified using fluorescence correlation spectroscopy

Mittag¹,

Milani²,

Walsh

et al. 2014

Biochemical and Biophysical Research Communications

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a b s t r a c tLow molecular weight oligomers of amyloid beta (Ab) are important drivers of Alzheimer's disease. A decrease in Ab monomer levels in human cerebrospinal fluid (CSF) is observed in Alzheimers' patients and is a robust biomarker of the disease. It has been suggested that the decrease in monomer levels in CSF is due to the formation of Ab oligomers. A robust technique capable of identifying Ab oligomers in CSF is therefore desirable. We have used fluorescence correlation spectroscopy and a five Gaussian distribution model (5GDM) to monitor the aggregation of Ab 1-42 in sodium phosphate buffer and in artificial cerebrospinal fluid (ACSF). In buffer, several different sized components (monomer, oligomers, protofibrils and fibrils) can be identified simultaneously using 5GDM. In ACSF, the faster kinetics of fibrillogenesis leads to the formation of fibrils on very short timescales. This analysis method can also be used to monitor the aggregation of other proteins, nanoparticles or colloids, even in complex biological fluids.

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“…S3). The presence of fibrils is consistent with 5GDM analysis and the size values obtained for fibrils are in agreement with published studies [5,42,43].…”

Section: Evaluation Of the Four Fractions Of Ab 1-42 Aggregatessupporting

confidence: 93%

Simultaneous measurement of a range of particle sizes during Aβ1–42 fibrillogenesis quantified using fluorescence correlation spectroscopy

Mittag¹,

Milani²,

Walsh

et al. 2014

Biochemical and Biophysical Research Communications

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“…Within the amyloid field, it is widely accepted that oligomeric species are potentially more toxic than mature fibrils (17)(18)(19)(20). However, toxicity associated with amyloid fibrils may also be pathologically relevant.…”

Section: Light Chain (Al)mentioning

confidence: 99%

Cell Damage in Light Chain Amyloidosis

Argany¹,

Lin²,

Misra³

et al. 2016

Journal of Biological Chemistry

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Light chain (AL) amyloidosis is an incurable human disease characterized by the misfolding, aggregation, and systemic deposition of amyloid composed of immunoglobulin light chains (LC). This work describes our studies on potential mechanisms of AL cytotoxicity. We have studied the internalization of AL soluble proteins and amyloid fibrils into human AC16 cardiomyocytes by using real time live cell image analysis. Our results show how external amyloid aggregates rapidly surround the cells and act as a recruitment point for soluble protein, triggering the amyloid fibril elongation. Soluble protein and external aggregates are internalized into AC16 cells via macropinocytosis. AL amyloid fibrils are shown to be highly cytotoxic at low concentrations. Additionally, caspase assays revealed soluble protein induces apoptosis, demonstrating different cytotoxic mechanisms between soluble protein and amyloid aggregates. This study emphasizes the complex immunoglobulin light chain-cell interactions that result in fibril internalization, protein recruitment, and cytotoxicity that may occur in AL amyloidosis. Light chain (AL)2 amyloidosis is a protein misfolding disease characterized by extracellular deposition of immunoglobulin light chains (LC) as amyloid fibrils. LC proteins are comprised of two distinct domains: the variable (V L ) and constant (C L ) domains (also called LC full-length (FL) protein to differentiate with the V L domain). In patients with AL amyloidosis, the LC aggregate and deposit in vital organs, causing organ failure and death (1). The factors governing deposition in individual tissues are unknown. Patients with cardiac AL amyloidosis have the worst prognosis, with a median survival of less than a year (2, 3).The finding that the V L was the primary component of amyloid fibrils influenced previous biophysical studies (4,5). Recent proteomic studies have demonstrated that amyloid deposits are likely heterogeneous in nature and can be formed by FL, V L , C L , or mixtures of all types of LC fragments (6 -8). Thermodynamic studies proposed a stabilizing role for the 3C L domain in the stability and a modulating effect on fibril formation (9). Recently, our laboratory has demonstrated that the C L domain modulates the amyloid formation reaction but has no effect on the stability of the protein (10).Soluble monoclonal LC, isolated from patients with amyloidosis, can impair rat cardiomyocyte function (11) and induce apoptotic events in mouse cardiomyocytes (12, 13). Also, urinederived LC can be internalized into primary rat cardiac fibroblasts (14) and primary human renal mesangial cells (15) through a pinocytic pathway (16) or via receptor, clathrin-mediated mechanisms, respectively (15).Within the amyloid field, it is widely accepted that oligomeric species are potentially more toxic than mature fibrils (17-20). However, toxicity associated with amyloid fibrils may also be pathologically relevant. Engel et al. (21) described a mechanism in which growth of islet amyloid associated polypeptides fibrils is re...

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“…They interfere with multiple cellular mechanisms, disrupt cell membranes, and eventually may cause cell death, all of which are mediated by mechanisms that are not well understood and are actively investigated [2]. The oligomers are metastable structures that are difficult to detect, isolate, and study even on their own, let alone in the complex context of a cell or a tissue.…”

mentioning

confidence: 99%

Modulators of amyloid protein aggregation and toxicity: EGCG and CLR01

Attar

Rahimi

Bitan

2013

Translational Neuroscience

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Abnormal protein folding and self-assembly causes over 30 cureless human diseases for which no diseasemodifying therapies are available. The common side to all these diseases is formation of aberrant toxic protein oligomers and amyloid fibrils. Both types of assemblies are drug targets, yet each presents major challenges to drug design, discovery, and development. In this review, we focus on two small molecules that inhibit formation of toxic amyloid protein assemblies -the green-tea derivative (-)-epigallocatechin-3-gallate (EGCG), which was identified through a combination of epidemiologic data and a compound library screen, and the molecular tweezer CLR01, whose inhibitory activity was discovered in our group based on rational reasoning, and subsequently confirmed experimentally. Both compounds act in a manner that is not specific to one particular protein and thus are useful against a multitude of amyloidogenic proteins, yet they act via distinct putative mechanisms. CLR01 disrupts protein aggregation through specific binding to lysine residues, whereas the mechanisms underlying the activity of EGCG are only recently beginning to unveil. We discuss current in vitro and, where available, in vivo literature related to EGCG and CLR01's effects on amyloid β-protein, α-synuclein, transthyretin, islet amyloid polypeptide, and calcitonin. We also describe the toxicity, pharmacokinetics, and mechanism of action of each compound.

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Oligomeric Intermediates in Amyloid Formation: Structure Determination and Mechanisms of Toxicity

Cited by 310 publications

References 152 publications

Simultaneous measurement of a range of particle sizes during Aβ1–42 fibrillogenesis quantified using fluorescence correlation spectroscopy

Simultaneous measurement of a range of particle sizes during Aβ1–42 fibrillogenesis quantified using fluorescence correlation spectroscopy

Cell Damage in Light Chain Amyloidosis

Modulators of amyloid protein aggregation and toxicity: EGCG and CLR01

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