Multifunctional roles of zinc in Alzheimer’s disease

•Systematically reviewed the function of zinc ions in the development of AD.•Summarized zinc-binding proteins and their effects on AD pathology of zinc-binding.•Summarized the trend of zinc content in different cerebral regions of AD patients. Zinc is the second abundant trace element in the human central nervous system (CNS). Zinc homeostasis is impaired in the elderly population and Alzheimer’s disease (AD) patients. Due to the failures of β-amyloid (Aβ)- and microtubule-associated protein tau (MAP-tau, tau)-targeting drugs, many researchers consider AD as a multifactorial disease. Emerging evidence demonstrates that zinc is also widely associated with the development of AD. Zinc dyshomeostasis hypothesis of AD has been proposed. In this review, we summarize the role of zinc in Aβ production, protein quality control, redox homeostasis, tau phosphorylation, and BDNF signaling. Due to the multifunctional roles of zinc, when zinc dyshomeostasis occurs, it may influence these different biological activities. Zinc dyshomeostasis could be a therapeutic target for AD treatment. However, there is no consensus on the zinc concentration alteration and the effect of zinc overload or zinc deficiency in AD patients, mouse models and cell lines. Given these significant differences across reported studies, it still needs a long time for clinical application in the treatment of AD.