P1‐422: Abeta neurotoxicity is modulated by the rate of peptide aggregation: Abeta dimers and trimers correlate with neurotoxicity

Hung, Lin W.; Ciccotosto, Giuseppe D.; Giannakis, Eleni; Tew, Deborah J.; Perez, Keyla; Masters, Colin L.; Cappai, Roberto; Wade, John D.; Barnham, Kevin J.

doi:10.1016/j.jalz.2008.05.1004

Cited by 30 publications

(40 citation statements)

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“…Another interesting consideration in relation to this study is that soluble and aggregated A␤ have differing membrane-binding capabilities, with soluble, intermediate-sized species of A␤ binding strongly to lipid membranes, an event required for A␤-induced neurotoxicity (Hung et al, 2008). Thus, the authors' observation of increased cholesterol in mature neurons might represent an increased binding surface for A␤, contributing to the neuronal death observed only after maturation of neurons in culture.…”

Section: Review Of Nicholson and Ferreiramentioning

confidence: 88%

“…Cholesterol and sphingolipids are enriched in lipid rafts, which function as signal transduction platforms in neurons, and are a major site of A␤ production (Hung et al, 2008). Several laboratories have demonstrated that key neuronal proteins involved in calcium transport and signaling are also localized in these compartments.…”

Section: Review Of Nicholson and Ferreiramentioning

confidence: 99%

See 1 more Smart Citation

Linking Amyloid and Tau Pathology in Alzheimer's Disease: The Role of Membrane Cholesterol in Aβ-Mediated Tau Toxicity: Figure 1.

Wray¹,

Noble²

2009

J. Neurosci.

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Section: Review Of Nicholson and Ferreiramentioning

confidence: 88%

Section: Review Of Nicholson and Ferreiramentioning

confidence: 99%

Linking Amyloid and Tau Pathology in Alzheimer's Disease: The Role of Membrane Cholesterol in Aβ-Mediated Tau Toxicity: Figure 1.

Wray¹,

Noble²

2009

J. Neurosci.

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“…PCA was undertaken using an Ab 42cc target with sequences corresponding to Ab [15][16][17][18][19][20][21] (QKLVFFA) Ab [29][30][31][32][33][34][35] (GAIIGLM), and Ab 36-42 (VGGVVIA) as library templates. The first of these two regions are known to aggregate into toxic fibrils in isolation [16][17][18] and therefore provided a strong starting point for deriving peptides known to bind to Ab 42cc and potentially capable of inhibiting aggregation.…”

Section: Library Generationmentioning

confidence: 99%

“…The first of these two regions are known to aggregate into toxic fibrils in isolation [16][17][18] and therefore provided a strong starting point for deriving peptides known to bind to Ab 42cc and potentially capable of inhibiting aggregation. Figure 1.…”

Section: Library Generationmentioning

confidence: 99%

Intracellular selection of peptide inhibitors that target disulphide‐bridged Aβ₄₂ oligomers

et al. 2014

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The b-amyloid (Ab) peptide aggregates into a number of soluble and insoluble forms, with soluble oligomers thought to be the primary factor implicated in Alzheimer's disease pathology. As a result, a wide range of potential aggregation inhibitors have been developed. However, in addition to problems with solubility and protease susceptibility, many have inadvertently raised the concentration of these soluble neurotoxic species. Sandberg et al. previously reported a b-hairpin stabilized variant of Ab 42 that results from an intramolecular disulphide bridge (A21C/A31C; Ab 42cc ), which generates highly toxic oligomeric species incapable of converting into mature fibrils. Using an intracellular protein-fragment complementation (PCA) approach, we have screened peptide libraries using E. coli that harbor an oxidizing environment to permit cytoplasmic disulphide bond formation. Peptides designed to target either the first or second b-strand have been demonstrated to bind to Ab 42cc , lower amyloid cytotoxicity, and confer bacterial cell survival. Peptides have consequently been tested using wild-type Ab 42 via ThT binding assays, circular dichroism, MTT cytotoxicity assays, fluorescence microscopy, and atomic force microscopy. Results demonstrate that amyloid-PCA selected peptides function by both removing amyloid oligomers as well as inhibiting their formation. These data further support the use of semirational design combined with intracellular PCA methodology to develop Ab antagonists as candidates for modification into drugs capable of slowing or even preventing the onset of AD.

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“…[8][9][10][11][12][13][14] Since the process of Aβ oligomerization is very dynamic, it was suggested that neurotoxicity is induced by various Aβo instead of only one specific type of oligomer. [14][15][16] Since many studies have shown that Aβo can initiate synapse dysfunctions prior to synapse and neuronal loss, [17][18][19][20][21][22][23][24] current theories indicate that Aβ-related treatment might be effective in early AD rather than at later stages as tested so far in clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Neurodegeneration in an Animal Model of Chronic Amyloid-beta Oligomer Infusion Is Counteracted by Antibody Treatment Infused with Osmotic Pumps

Sajadi

Provost

Pham

et al. 2016

JoVE

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Decline in hippocampal-dependent explicit memory (memory for facts and events) is one of the earliest clinical symptom of Alzheimer's disease (AD). It is well established that synapse loss and ensuing neurodegeneration are the best predictors for memory impairments in AD. Latest studies have emphasized the neurotoxic role of soluble amyloid-beta oligomers (Aβo) that begin to accumulate in the human brain approximately 10 to 15 yr before the clinical symptoms become apparent. Many reports indicate that soluble Aβo correlate with memory deficits in AD models and humans. The Aβo-induced neurodegeneration observed in neuronal and brain slice cultures has been more challenging to reproduce in many animal models. The model of repeated Aβo infusions shown here overcome this issue and allow addressing two key domains for developing new disease modifying therapies: identify biological markers to diagnose early AD, and determine the molecular mechanisms underpinning Aβo-induced memory deficits at the onset of AD. Since soluble Aβo aggregate relatively fast into insoluble Aβ fibrils that correlate poorly with the clinical state of patients, soluble Aβo are prepared freshly and injected once per day during six days to produce marked cell death in the hippocampus. We used cannula specially design for simultaneous infusions of Aβo and continuous infusion of Aβo antibody (6E10) in the hippocampus using osmotic pumps. This innovative in vivo method can now be used in preclinical studies to validate the efficiency of new AD therapies that might prevent the deposition and neurotoxicity of Aβo in pre-dementia patients.

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P1‐422: Abeta neurotoxicity is modulated by the rate of peptide aggregation: Abeta dimers and trimers correlate with neurotoxicity

Cited by 30 publications

References 0 publications

Linking Amyloid and Tau Pathology in Alzheimer's Disease: The Role of Membrane Cholesterol in Aβ-Mediated Tau Toxicity: Figure 1.

Linking Amyloid and Tau Pathology in Alzheimer's Disease: The Role of Membrane Cholesterol in Aβ-Mediated Tau Toxicity: Figure 1.

Intracellular selection of peptide inhibitors that target disulphide‐bridged Aβ₄₂ oligomers

Neurodegeneration in an Animal Model of Chronic Amyloid-beta Oligomer Infusion Is Counteracted by Antibody Treatment Infused with Osmotic Pumps

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P1‐422: Abeta neurotoxicity is modulated by the rate of peptide aggregation: Abeta dimers and trimers correlate with neurotoxicity

Cited by 30 publications

References 0 publications

Linking Amyloid and Tau Pathology in Alzheimer's Disease: The Role of Membrane Cholesterol in Aβ-Mediated Tau Toxicity: Figure 1.

Linking Amyloid and Tau Pathology in Alzheimer's Disease: The Role of Membrane Cholesterol in Aβ-Mediated Tau Toxicity: Figure 1.

Intracellular selection of peptide inhibitors that target disulphide‐bridged Aβ42 oligomers

Neurodegeneration in an Animal Model of Chronic Amyloid-beta Oligomer Infusion Is Counteracted by Antibody Treatment Infused with Osmotic Pumps

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Intracellular selection of peptide inhibitors that target disulphide‐bridged Aβ₄₂ oligomers