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Effect of poly(propylene imine) glycodendrimers on β-amyloid aggregation in vitro and in APP/PS1 transgenic mice, as a model of brain amyloid deposition and Alzheimer's disease

Klementieva, O LU ; Aso, E; Filippini, D; Benseny-Cases, N; Carmona, M; Juvés, S; Appelhans, D; Cladera, J and Ferrer, I (2013) In Biomacromolecules 14(10). p.80-3570
Abstract

Poly(propylene imine) (PPI) glycodendrimers are promising candidates as drug carriers and antiamyloidogenic and antiprionic agents. In this study the anti-β-amyloid capacity of PPI glycodendrimers of the fourth and fifth generations was investigated in vitro and in vivo. We assessed distinct PPI glycodendrimers including G4mDS and G5mDS, with electroneutral maltose shell, and G4mOS and G4m-IIIOS, with cationic maltose or maltotriose shell. Our results show that in vitro PPI maltose dendrimers reduce the toxicity of Aβ(1-42). However, only the electroneutral maltose dendrimers G4mDS and G5mDS reduce the toxicity of Alzheimer's disease brain extracts in SH-SY5Y neuroblastoma cells. PPI maltose dendrimers with electroneutral or cationic... (More)

Poly(propylene imine) (PPI) glycodendrimers are promising candidates as drug carriers and antiamyloidogenic and antiprionic agents. In this study the anti-β-amyloid capacity of PPI glycodendrimers of the fourth and fifth generations was investigated in vitro and in vivo. We assessed distinct PPI glycodendrimers including G4mDS and G5mDS, with electroneutral maltose shell, and G4mOS and G4m-IIIOS, with cationic maltose or maltotriose shell. Our results show that in vitro PPI maltose dendrimers reduce the toxicity of Aβ(1-42). However, only the electroneutral maltose dendrimers G4mDS and G5mDS reduce the toxicity of Alzheimer's disease brain extracts in SH-SY5Y neuroblastoma cells. PPI maltose dendrimers with electroneutral or cationic surface penetrate the cytoplasm of cultured cells, and they reach the brain when administered intranasally. Both cationic G4mOS and electroneutral G4mDS are able to modify the total burden of β-amyloid in APP/PS1 mice. The studied dendrimers did not reverse memory impairment in APP/PS1 mice following chronic administration; moreover, cationic G4mOS caused cognitive decline in nontransgenic mice. In spite of the capacity of G4mDS and G4mOS to cross the blood-brain barrier and modulate Aβ aggregation in APP/PS1 mice, further studies are needed to learn how to reduce the harmful effects of maltose dendrimers in vivo.

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author
publishing date
type
Contribution to journal
publication status
published
keywords
Administration, Intranasal, Alzheimer Disease/drug therapy, Amyloid beta-Protein Precursor/genetics, Animals, Brain/drug effects, Cell Survival/drug effects, Dendrimers/administration & dosage, Disease Models, Animal, Dose-Response Relationship, Drug, Glycoconjugates/administration & dosage, Humans, Male, Maltose/chemistry, Mice, Mice, Transgenic, Particle Size, Polypropylenes/administration & dosage, Protein-Serine-Threonine Kinases/genetics, Structure-Activity Relationship, Surface Properties, Tumor Cells, Cultured
in
Biomacromolecules
volume
14
issue
10
pages
80 - 3570
publisher
The American Chemical Society
external identifiers
  • scopus:84885605499
ISSN
1526-4602
DOI
10.1021/bm400948z
language
English
LU publication?
no
id
33d0b5b1-16be-4601-84e8-53d9a429970f
date added to LUP
2018-11-01 13:24:58
date last changed
2019-03-19 04:01:58
@article{33d0b5b1-16be-4601-84e8-53d9a429970f,
  abstract     = {<p>Poly(propylene imine) (PPI) glycodendrimers are promising candidates as drug carriers and antiamyloidogenic and antiprionic agents. In this study the anti-β-amyloid capacity of PPI glycodendrimers of the fourth and fifth generations was investigated in vitro and in vivo. We assessed distinct PPI glycodendrimers including G4mDS and G5mDS, with electroneutral maltose shell, and G4mOS and G4m-IIIOS, with cationic maltose or maltotriose shell. Our results show that in vitro PPI maltose dendrimers reduce the toxicity of Aβ(1-42). However, only the electroneutral maltose dendrimers G4mDS and G5mDS reduce the toxicity of Alzheimer's disease brain extracts in SH-SY5Y neuroblastoma cells. PPI maltose dendrimers with electroneutral or cationic surface penetrate the cytoplasm of cultured cells, and they reach the brain when administered intranasally. Both cationic G4mOS and electroneutral G4mDS are able to modify the total burden of β-amyloid in APP/PS1 mice. The studied dendrimers did not reverse memory impairment in APP/PS1 mice following chronic administration; moreover, cationic G4mOS caused cognitive decline in nontransgenic mice. In spite of the capacity of G4mDS and G4mOS to cross the blood-brain barrier and modulate Aβ aggregation in APP/PS1 mice, further studies are needed to learn how to reduce the harmful effects of maltose dendrimers in vivo. </p>},
  author       = {Klementieva, O and Aso, E and Filippini, D and Benseny-Cases, N and Carmona, M and Juvés, S and Appelhans, D and Cladera, J and Ferrer, I},
  issn         = {1526-4602},
  keyword      = {Administration, Intranasal,Alzheimer Disease/drug therapy,Amyloid beta-Protein Precursor/genetics,Animals,Brain/drug effects,Cell Survival/drug effects,Dendrimers/administration & dosage,Disease Models, Animal,Dose-Response Relationship, Drug,Glycoconjugates/administration & dosage,Humans,Male,Maltose/chemistry,Mice,Mice, Transgenic,Particle Size,Polypropylenes/administration & dosage,Protein-Serine-Threonine Kinases/genetics,Structure-Activity Relationship,Surface Properties,Tumor Cells, Cultured},
  language     = {eng},
  month        = {10},
  number       = {10},
  pages        = {80--3570},
  publisher    = {The American Chemical Society},
  series       = {Biomacromolecules},
  title        = {Effect of poly(propylene imine) glycodendrimers on β-amyloid aggregation in vitro and in APP/PS1 transgenic mice, as a model of brain amyloid deposition and Alzheimer's disease},
  url          = {http://dx.doi.org/10.1021/bm400948z},
  volume       = {14},
  year         = {2013},
}