Photolytic disruption of Alzheimer’s amyloid Aβ42-fibrils by sialic-acid decorated glycodendrimers

The formation of amyloid Aβ42-fibrils is linked to the pathology of cognitive dysfunction in Alzheimer’s patients. There is a dire need for developing therapeutics to reverse Aβ42 fibrillation and to stop or slow down the disease progression. Here, we report rationally designed sialic acid functionalized porphyrin cored first and second-generation dendrimers, synthesized using “click chemistry.” The glycoporphyrin dendrimer shows a promising ability to degrade Aβ42 fibrils to lower-order soluble oligomers upon irradiation. The gradual fragmentation of the β-sheet-rich Aβ42 fibrils to the unstructured forms by photoactivation of the dendrimers is evident from high-resolution imaging, particle size analysis, and peptide secondary structure distribution. Further, the glycodendrimers are non-toxic even when irradiated and can rescue the neuroblastoma cells from Aβ42 fibril-mediated cytotoxicity. We propose that the photoirradiated dendrimers degrade the Aβ42 fibrils by rupturing the H-bonds by the singlet oxygen species (ROS) generated from the excited porphyrin core. The formation of amyloid Aβ42-fibrils is linked to the pathology of cognitive dysfunction in Alzheimer’s patients and therapeutics that can reverse Aβ42 fibrillation are needed. Here, the authors use click chemistry to design sialic acid functionalized porphyrin cored first and second-generation dendrimers that show a promising ability to disrupt Aβ42 fibrils to lower-order soluble oligomers upon irradiation.