TDMQ20, a Specific Copper Chelator, Reduces Memory Impairments in Alzheimer's Disease Mouse Models

Besides targeting amyloid or tau metabolisms, regulation of redox metal ions is a recognized therapeutic target for Alzheimer's disease (AD). Based on the bioinorganic chemistry of copper, we designed specific chelators of copper(II) (TDMQs) insight to regulate copper homeostasis in the brain and to inhibit the deleterious oxidative stress catalyzed by copper-amyloid complexes. An oral treatment by TDMQ20 was able to fully reverse the cognitive and behavioral impairment in three different murine models, two nontransgenic models mimicking the early stage of AD and a transgenic model representing a more advanced stage of AD. To our knowledge, such a comparative study using the same molecule has never been performed. Regular C57BL/6 mice received a single injection of humanCu-A ss(1-42) in the lateral ventricles (icv-CuA ss) or in the hippocampus (hippo-CuA ss). In both cases, mice developed a cognitive impairment similar to that of transgenic 5XFAD mice. Oral administration of TDMQ20 to icv-CuA ss or hippo-CuA ss mice within a 16-day period resulted in a significant improvement of the cognitive status. The 3-month treatment of transgenic 5XFAD mice with TDMQ20 also resulted in behavioral improvements. The consistent positive pharmacological results obtained using these different AD models correlate well with previously obtained physicochemical data of TDMQ20. The short-term novel object recognition (NOR) test was found particularly relevant to evaluate the rescue of declarative memory impairment. TDMQ20 was also able to reduce the oxidative stress in the mouse cortex. Due to its reliability and facile use, the hippo-CuA ss model can be considered as a robust nontransgenic model to evaluate the activity of potential drugs on the early stages of memory deficits. [Graphics]

Automated summary

Regulation of redox metal ions, such as copper, presents a promising therapeutic approach for Alzheimer's disease. Specific copper(II) chelators like TDMQ20 show potential in improving cognitive and behavioral impairments in various AD mouse models, as well as reducing oxidative stress and enhancing memory function. The positive pharmacological results obtained from different AD models suggest the efficacy of TDMQ20 in treating AD-related symptoms and memory deficits.