Glycosaminoglycan model polymers with Poly(γ-glutamate) backbone to inhibit aggregation of β-Amyloid peptide

Alzheimer's disease is a serious dementia frequently accompanied by the emergence of senile plaques in the cerebral mesothelium. Senile plaques involve pathogenic aggregates of β-amyloid peptide (Aβ) with a β-sheet structure.¹ Aβ aggregates deposit on the cell via interactions with extracellular matrices such as glycosaminoglycans (GAGs). GAGs have received much attention with respect to Alzheimer's disease pathogenesis, and it has been found that the amount of bound Aβ is related to the GAG structure.^{2, 3, 4} GAGs have a negative net charge based on the sulfate group and carboxyl group on the saccharide. The biological activities of GAGs vary according to the saccharide structure in the GAG; such activities include interactions with Aβ, and these cause Aβ intricate changes. Although the addition of GAGs inhibits the aggregation of Aβ in some cases, GAGs sometimes induce Aβ aggregation, with conformational changes.^{5, 6, 7, 8} It is important to clarify the complex biological activity of GAGs in order to elucidate the pathogenic mechanism with respect to Aβ and to develop medicinal compounds based on GAGs. It has been reported that heparin, which is a GAG, inhibits Aβ aggregation as a result of the electrostatic interactions between the anionic sulfate group of heparin and the cationic domain of Aβ13–16(HHQK).⁹ The abundant sulfate groups of heparin and other GAGs are the key to their interactions with Aβ, but the interactions between GAGs and Aβ are difficult to analyze because GAGs have complicated saccharide structures and high molecular weights. To overcome the difficulties of GAG analysis and enable facile development of therapeutic materials, we previously investigated GAG-mimicking polymers with multivalent sulfated saccharides, and reported that glycopolymers with sulfonated saccharides interacted with Aβ and controlled its aggregation.^{10, 11, 12} The usage of GAGs mimic with well-ordered structures and molecular weights helped to analyze the molecular interaction in detail, and we have clarified that Aβ binds to sulfonated saccharides by electrostatic interactions. We also prepared GAG-mimicking polymers with multivalent uronic acids (a sugar with a carboxylic acid group) and found that the carboxylic acid on uronic acid also delays elongation in Aβ aggregation.¹¹ A glyco-copolymer of uronic acid and a sulfated saccharide, which showed strong inhibition of Aβ activity, has been synthesized. These results indicated that GAG-mimicking polymers with two anionic groups, namely carboxylic acid and sulfate groups, are good inhibitors for Aβ. These glycopolymers had an acrylamide backbone and were synthesized via radical polymerization. Synthesis of glycopolymers by radical polymerization is a facile method of preparing versatile GAG-mimicking polymers.¹³ However, it was suspected that the biocompatibility of the synthetic polyacrylamide backbone was insufficient.¹⁴

In this research, we focused on the synthesis and properties of novel GAG-mimicking polymers with a poly(γ-glutamate) (PGA) backbone. PGA is known to have good biocompatibility. As PGA is a natural product, not only PGA itself but also PGA hydrolysates are biocompatible.^{15, 16} In addition, PGA is highly water soluble, which is appropriate for polymeric drugs. The important point of this study is the use of PGA as a glycopolymer backbone because of its biocompatibility. We modified PGA with p-nitrophenyl-6-sulfo-N-acetyl-D-glucosamine (6S-GlcNAc: 0-A) and taurine to give GAG-mimicking polymers with both carboxyl and sulfate groups, and studied the inhibitory effects of the GAG-mimicking PGA polymers.

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