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

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 t...

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Published in:Experimental neurology 2024-03, Vol.373, p.114657-114657, Article 114657
Main Authors: Zuo, Yue, Liu, Hui-ting, Lin, Lai-biao, Yue, Rui-zhu, Liu, Huan-huan, Wang, Hong-wei, Wang, Lu, Hou, Ruan-ling, Liu, Wei-zhen, Li, Chang-zheng, Wang, Jian-Zhi, Li, Peng, Yin, Ya-ling
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Language:English
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Summary: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. [Display omitted] •The overexpression of full-length human tau protein leads to a disruption in the balance of iron ion.•Iron deposition triggers CaN activation, leading to CREB dephosphorylation, synaptic deficits, and memory impairment.•Iron deposition worsens hyperphosphorylation of tau protein, mediated by GSK-3β enzyme dephosphorylated by CaN.•We have developed DpdtpA, an iron-chelating agent, which reduces tau hyperphosphorylation and improves memory.•These findings provide new insights into the mechanisms of memory impairment induced by Tau accumulation.
ISSN:0014-4886
1090-2430
DOI:10.1016/j.expneurol.2023.114657