A new metal ion chelator attenuates human tau accumulation-induced neurodegeneration and memory deficits in mice

Exp Neurol. 2024 Mar:373:114657. doi: 10.1016/j.expneurol.2023.114657. Epub 2023 Dec 22.


Neuronal neurofibrillary tangles containing Tau hyperphosphorylation proteins are a typical pathological marker of Alzheimer's disease (AD). The level of tangles in neurons correlates positively with severe dementia. However, how Tau induces cognitive dysfunction is still unknown, which leads to a lack of effective treatments for AD. Metal ions deposition occurs with tangles in AD brain autopsy. Reduced metal ion can improve the pathology of AD. To explore whether abnormally phosphorylated Tau causes metal ion deposition, we overexpressed human full-length Tau (hTau) in the hippocampal CA3 area of mice and primary cultured hippocampal neurons (CPHN) and found that Tau accumulation induced iron deposition and activated calcineurin (CaN), which dephosphorylates glycogen synthase kinase 3 beta (GSK3β), mediating Tau hyperphosphorylation. Simultaneous activation of CaN dephosphorylates cyclic-AMP response binding protein (CREB), leading to synaptic deficits and memory impairment, as shown in our previous study; this seems to be a vicious cycle exacerbating tauopathy. In the current study, we developed a new metal ion chelator that displayed a significant inhibitory effect on Tau phosphorylation and memory impairment by chelating iron ions in vivo and in vitro. These findings provide new insight into the mechanism of memory impairment induced by Tau accumulation and develop a novel potential treatment for tauopathy in AD.

Keywords: Alzheimer's disease; CREB; Calcineurin; GSK3β; Tau; iron.

MeSH terms

  • Alzheimer Disease* / metabolism
  • Animals
  • Chelating Agents / pharmacology
  • Chelating Agents / therapeutic use
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Humans
  • Ions
  • Iron
  • Memory Disorders / drug therapy
  • Memory Disorders / etiology
  • Mice
  • Mice, Transgenic
  • Phosphorylation
  • Tauopathies* / pathology
  • tau Proteins / metabolism


  • tau Proteins
  • Chelating Agents
  • Ions
  • Iron
  • Glycogen Synthase Kinase 3 beta