Abstract

Alzheimer’s disease (AD), the most common form of dementia, is characterized by progressive neuronal and synaptic degeneration, leading to cognitive and motor impairment and ultimately death. AD pathology arises from multiple interconnected processes, including (i) the deposition of senile plaques and neurofibrillary tangles, composed of amyloid-β (Aβ) aggregates and hyperphosphorylated tau aggregates, respectively; (ii) metal-ion dyshomeostasis and miscompartmentalization; and (iii) oxidative stress driven by excessive production of reactive oxygen species (ROS).^1-3 Although individual links among these pathological features have been investigated, their integrated roles in AD pathogenesis remain poorly defined. Metal ions interact with Aβ and tau, contributing to aggregation, toxicity, and oxidative stress, while ROS further promote the formation and pathological remodeling of Aβ and tau assemblies. ^1-3 To elucidate the interplay among these pathogenic elements underlying AD-associated toxicity, we have developed chemical tools that simultaneously target and regulate multiple pathological factors^4-10 and have delineated pathogenic networks arising from their direct interactions and chemical reactivities.^11-15

References

1. Acc. Chem. Res. 2014, 47, 2475; Acc. Chem. Res. 2021, 54, 3930.

2. Chem. Rev. 2019, 119, 1221.

3. Coord. Chem. Rev. 2023, 478, 214978.

4.  Proc. Natl. Acad. Sci. USA 2010, 107, 21990; Chem. Sci. 2015, 6, 1879.

5.  J. Am. Chem. Soc. 2014, 136, 299.

6.  J. Am. Chem. Soc. 2015, 137, 14785.

7.  Nat. Commun. 2016, 7, 13115.

8. Proc. Natl. Acad. Sci. USA 2020, 117, 5160.

9. J. Am. Chem. Soc. 2020, 142, 8183.

10. J. Am. Chem. Soc. 2026, 148, 461.

11. Nature Chem. 2022, 14, 1021.

12. Adv. Sci. 2024, 11, 2307182.

13. Nature Chem. Biol. 2025, 21, 1709.

14. ACS Cent. Sci. 2026, 12, 1659.

15. Adv. Sci. 2026, In Press.