Multifunctional molecular agent for tau-targeted combinational therapy of Alzheimer's disease

Tau aggregation inhibitors or neurotoxic-metal chelators have been extensively studied as potential treatment for Alzheimer's disease. However, it is a great challenge to improve their therapeutic effects while reducing neurotoxicity. Herein, we designed and synthesized two new compounds, (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetrakis((3,4,5-trihydroxyphenyl)methanone) (4GA) and (4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis((3,4,5-trihydroxyphenyl)methanone) (2GA). Each molecule is composed of a 1,4,7,10-tetraazacyclododecane (cyclen) core as the supramolecular chelator to copper ions, attached by 2 or 4GAllic acid polyphenol arms to capture tau peptide chain like a molecular hairpin. We interestingly found that 4GA and 2GA could inhibit self-aggregation through blocking the misfolding of tau peptide, suppress the promotion of Cu²⁺ on tau aggregation by removing Cu²⁺ from dyshomeostasis, and clear reactive oxygen species triggered by Cu²⁺ using their reductive gallic acid groups. More significantly, the synthesized compounds exhibit remarkable efficiency on both in vitro and at cellular level. Our rational design of multifunctional therapeutic agent that simultaneously targets tau misfolding process, copper dyshomeostasis, and oxidative stress of reactive oxygen species, may hold considerable implications for the treatment of Alzheimer's disease.