Influence of heparin and dendrimers on the aggregation of two amyloid peptides related to Alzheimer’s and prion diseases

Klajnert, Barbara; Cortijo-Arellano, Marta; Bryszewska, Maria; Cladera, Josep

doi:10.1016/j.bbrc.2005.11.053

Cited by 113 publications

(115 citation statements)

References 32 publications

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“…[33][34][35][36] Ab aggregation was inhibited by third-generation amine-terminated polyamine dendrimers, and the inhibition increased with A C H T U N G T R E N N U N G increasing dendrimer concentration and generation. To show that the multivalent effect of K 4 was specifically caused by the KLVFF sequence and not by the dendritic structure itself, we performed similar aggregation assays with a dendrimer that consisted of 4 unrelated pentapeptides (G 4 ).…”

Section: Discussionmentioning

confidence: 98%

“…The potency of a multivalent KLVFF derivative might be enhanced by using a higher generation dendrimer, but this is likely to also enhance sequence-unspecific effects, as observed with the third and higher generation amine-terminated polyamine dendrimers. [34,35] In addition, with increasing generation, the hydrophobicity will increase, as well as its size and shape, thereby loosing the advantage of a soluble small-size inhibitor.…”

Section: Discussionmentioning

confidence: 99%

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Branched KLVFF Tetramers Strongly Potentiate Inhibition of β‐Amyloid Aggregation

et al. 2007

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The key pathogenic event in the onset of Alzheimer's disease (AD) is the aggregation of β‐amyloid (Aβ) peptides into toxic aggregates. Molecules that interfere with this process might act as therapeutic agents for the treatment of AD. The amino acid residues 16–20 (KLVFF) are known to be essential for the aggregation of Aβ. In this study, we have used a first‐generation dendrimer as a scaffold for the multivalent display of the KLVFF peptide. The effect of four KLVFF peptides attached to the dendrimer (K4) on Aβ aggregation was compared to the effect of monomeric KLVFF (K1). Our data show that K4 very effectively inhibits the aggregation of low‐molecular‐weight and protofibrillar Aβ1–42 into fibrils, in a concentration‐dependent manner, and much more potently than K1. Moreover, we show that K4 can lead to the disassembly of existing aggregates. Our data lead us to propose that conjugates that bear multiple copies of KLVFF might be useful as therapeutic agents for the treatment of Alzheimer's disease.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Branched KLVFF Tetramers Strongly Potentiate Inhibition of β‐Amyloid Aggregation

et al. 2007

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“…PAMAM, PPI and phosphorous dendrimers changed kinetic parameters of aggregation for the prion peptide PrP185-208, such as nucleation and elongation rate and reduced the final amount of amyloid fibrils formed [46][47][48][49] . A generation dependent effect on both the inhibition of fibril aggregation and the disruption of fibrils of the PrP185-208 peptide was observed for PAMAM dendrimers 48 .…”

Section: Introductionmentioning

confidence: 99%

Influence of Surface Functionality of Poly(propylene imine) Dendrimers on Protease Resistance and Propagation of the Scrapie Prion Protein

et al. 2010

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Accumulation of PrPSc , an insoluble and protease-resistant pathogenic isoform of the cellular prion protein (PrP C ) is a hallmark in prion diseases. Branched polyamines, including PPI (poly(propylene imine)) dendrimers are able to remove protease resistant PrP Sc and abolish infectivity, offering possible applications for therapy. These dendrimer types are thought to act through their positively charged amino surface groups. In the present study the molecular basis of the anti-prion activity of dendrimers was further investigated employing modified PPI dendrimers, in which the positively charged amino surface groups were substituted with neutral carbohydrate units of maltose (mPPI) or maltotriose (m3PPI). Modification of surface groups greatly reduced the toxicity associated with unmodified PPI, but did not abolish its anti-prion activity, suggesting that the presence of cationic surface groups is not essential for dendrimer action. PPI and mPPI dendrimer of generation 5 were equally effective in reducing levels of protease-resistant PrP Sc (PrP res ) in a dose-and time-dependent manner in ScN2a cells, and in preexisting aggregates in homogenates from infected brain. Solubility assays revealed that total levels of PrP Sc in scrapie infected mouse neuroblastoma (ScN2a) cells were reduced by mPPI. Coupled with the known ability of polyamino dendrimers to render protease-resistant PrP Sc in pre-existing aggregates of PrP Sc susceptible to proteolysis, these findings strongly suggest that within infected cells dendrimers reduce total amounts of PrP Sc by mediating its denaturation and subsequent elimination.

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“…30 Third, dendrimers can also be considered potential agents for the disaggregation of amyloid aggregates. 31 Different generations of poly(amidoamine) (PAMAM) dendrimers and both polypropylenimine and phosphorus dendrimers have been used successfully to disaggregate amyloid fibrils under different conditions. [31][32][33][34][35][36] Also, PAMAM dendrimers inhibited the fibrillation of α-synuclein, and this effect increased with both generation number and PAMAM concentration.…”

Section: -22mentioning

confidence: 99%

Nanomaterials in Stroke Treatment

Shcharbina

Shcharbin

Bryszewska

2013

Stroke

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Influence of heparin and dendrimers on the aggregation of two amyloid peptides related to Alzheimer’s and prion diseases

Cited by 113 publications

References 32 publications

Branched KLVFF Tetramers Strongly Potentiate Inhibition of β‐Amyloid Aggregation

Branched KLVFF Tetramers Strongly Potentiate Inhibition of β‐Amyloid Aggregation

Influence of Surface Functionality of Poly(propylene imine) Dendrimers on Protease Resistance and Propagation of the Scrapie Prion Protein

Nanomaterials in Stroke Treatment

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