Structural Biology of Alzheimer's Disease
Universitat Autònoma de Barcelona (UAB)

Thanks to an important number of international collaborations, we have actively participated in  proving that dendrimers interact with amyloids (see the 2016 review in Progreess in Polymer Science), although most of dendrimers assayed in amyloidogenic systems are toxic to cells. The development of glycodendrimers, poly (propylene imine) (PPI) dendrimers decorated with maltose (Mal), represents the possibility of using dendrimers with a low intrinsic toxicity. We have shown that fourth (PPI-G4-Mal) and fifth (PPI-G5-Mal) generation glycodendrimers have the capacity to interfere with Alzheimer’s amyloid peptide Ab(1-40) fibrilization. The interaction is generation dependent: PPI-G5-Mal blocks amyloid fibril formation generating granular non-fibrillar amorphous aggregates whereas PPI-G4-Mal generates clumped fibrils at low dendrimer-peptide ratios and amorphous aggregates at high ratios. Both PPI-G4-Mal and PPI-G5-Mal are non-toxic to PC12 and SH-SY5Y cells. PPI-G4-Mal reduces amyloid toxicity by clumping fibrils together, whereas amorphous aggregates are toxic to PC12 cells. The results show that glycodendrimers are promising non-toxic agents in the search for antiamyloidogenic compounds. Fibril clumping may be an anti-amyloid toxicity strategy.

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We have 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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In collaboration with Prof Dietmar Appelhans in Dresden and Prof Isidre Ferrer in Barcelona we have recently shown in preliminary experiments, that a modified glycodendrimer used for the tratment of a transgenic mouse Alzheimer's model has resulted in the recovery of cognitive habilties of the diseased mice.