The metal ion hypothesis of Alzheimer’s disease and the anti-neuroinflammatory effect of metal chelators

Alzheimer’s disease (AD), characterized by the β-amyloid protein (Aβ) deposition and tau hyperphosphorylation, is the most common dementia with uncertain etiology. The clinical trials of Aβ monoclonal antibody drugs have almost failed, giving rise to great attention on the other etiologic hypothesis regarding AD such as metal ions dysmetabolism and chronic neuroinflammation. Mounting evidence revealed that the metal ions (iron, copper, and zinc) were dysregulated in the susceptible brain regions of AD patients, which was highly associated with Aβ deposition, tau hyperphosphorylation, neuronal loss, as well as neuroinflammation. Further studies uncovered that iron, copper and zinc could not only enhance the production of Aβ but also directly bind to Aβ and tau to promote their aggregations. In addition, the accumulation of iron and copper could respectively promote ferroptosis and cuproptosis. Therefore, the metal ion chelators were recognized as promising agents for treating AD. This review comprehensively summarized the effects of metal ions on the Aβ dynamics and tau phosphorylation in the progression of AD. Furthermore, taking chronic neuroinflammation contributes to the progression of AD, we also provided a summary of the mechanisms concerning metal ions on neuroinflammation and highlighted the metal ion chelators may be potential agents to alleviate neuroinflammation under the condition of AD. Nevertheless, more investigations regarding metal ions on neuroinflammation should be taken into practice, and the effects of metal ion chelators on neuroinflammation should gain more attention. Running title: Metal chelators against neuroinflammation.