@article {19752, title = {GaOH-dendrimers remodel the conformation of Aβ oligomers and reduce their toxicity towards SH-SY5Y cells}, booktitle = {GENE2SKIN AND CHEM2NATURE FINAL CONFERENCES}, year = {2018}, month = {2018-10-31 00:00:00}, address = {Guimar{\~a}es, Portugal}, abstract = {

Abnormal protein aggregation is a hallmark of multiple devastating neurodegenerative disorders, such as Parkinson{\textquoteright}s or Alzheimer{\textquoteright}s diseases (AD). In the case of AD, its development is associated with changes in the brain parenchyma, namely the formation of: 1) extracellular deposits of beta-amyloid (Aβ); and 2) intracellular hyperphosphorylated neurofibrillary tangles of tau.1

The formation of the extracellular deposits consist of a cascade of events that lead to the aberrant assembly of Aβ oligomers, protofibrils and fibrils; events that are also observed in the abnormal aggregation of other amyloidogenic proteins.2 One of the possible targets to inhibit the self-assembly process of misfolded Aβ is through the hydrophobic binding of the Aβ beta-sheet forming motifs. It has been reported that polyphenols derived from epigallocatechin gallate are able to interact with the hydrophobic regions of Aβ, centred on the aminoacid positions 16-22 and 27-35.3-4

In fact, unpublished data from our group showed that natural polyphenols (vescalagin and castalagin with five gallic acid units) can reduce cell death, due a remodeling caused on the hydrophobic region of Aβ monomers/oligomers/fibril. Based on these results, we designed dendrimers displaying this type of moieties on their surface and tested them for their ability to modulate Aβ fibrillization.

To this purpose, we synthesized 1G0-GaOH core dendrimer (2 gallate units), 2G1-GaOH (6 gallate units) and 3G1-GaOH (9 gallate units), and evaluated their ability to inhibit the aggregation of Aβ using Thioflavin-T assay, circular dichroism, AFM and western blot. Our results show that these dendrimers are able to modulate the β-sheet content of the Aβ supramolecular assemblies and to reduce the size of the fibrils in a manner proportional to the number of gallic acid units present in the dendrimer. We also confirmed that 2G1-GaOH and 3G1-GaOH have the capacity of maintain SH-SY5Y cell viability, reducing the oligomeric Aβ assemblies in the cytoplasm of the cells. Overall, we demonstrate that the gallic acid-presenting dendrimers represent a promising nanotherapeutical tool able to modulate the toxicity of Aβ assemblies in the AD context.

}, keywords = {Alzheimer{\textquoteright}s diseases, natural polyphenols}, author = {Ara{\'u}jo, A. R. and Correa, J. and Fernandez-Megia, E. and Reis, R. L. and Pires, R. A.} }