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.
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 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.
authors.affiliation: Institute of Neuropathology, Pathologic Anatomy Service, IDIBELL-University Hospital Bellvitge , Feixa Llarga sn, 08907 L'Hospitalet de Llobregat, Spain.
authors.forename: O
authors.initials: O
authors.lastname: Klementieva
authors.forename: E
authors.initials: E
authors.lastname: Aso
authors.forename: D
authors.initials: D
authors.lastname: Filippini
authors.forename: N
authors.initials: N
authors.lastname: Benseny-Cases
authors.forename: M
authors.initials: M
authors.lastname: Carmona
authors.forename: S
authors.initials: S
authors.lastname: Juvés
authors.forename: D
authors.initials: D
authors.lastname: Appelhans
authors.forename: J
authors.initials: J
authors.lastname: Cladera
authors.forename: I
authors.initials: I
authors.lastname: Ferrer
mesh_terms: D000281:Administration, Intranasal; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D050091:Dendrimers / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006001:Glycoconjugates / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008320:Maltose / Q000737:chemistry; D051379:Mice; D008822:Mice, Transgenic; D010316:Particle Size; D011126:Polypropylenes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013499:Surface Properties; D014407:Tumor Cells, Cultured
chemical_list: D016564:Amyloid beta-Protein Precursor; D050091:Dendrimers; D006001:Glycoconjugates; D011126:Polypropylenes; C443641:poly(propyleneimine); D008320:Maltose; D017346:Protein Serine-Threonine Kinases