title: Synaptic released zinc promotes tau hyperphosphorylation by inhibition of protein phosphatase 2A (PP2A).
abstract: Hyperphosphorylated tau is the major component of neurofibrillary tangles in Alzheimer disease (AD), and the tangle distribution largely overlaps with zinc-containing glutamatergic neurons, suggesting that zinc released in synaptic terminals may play a role in tau phosphorylation. To explore this possibility, we treated cultured hippocampal slices or primary neurons with glutamate or Bic/4-AP to increase the synaptic activity with or without pretreatment of zinc chelators, and then detected the phosphorylation levels of tau. We found that glutamate or Bic/4-AP treatment caused tau hyperphosphorylation at multiple AD-related sites, including Ser-396, Ser-404, Thr-231, and Thr-205, while application of intracellular or extracellular zinc chelators, or blockade of zinc release by extracellular calcium omission almost abolished the synaptic activity-associated tau hyperphosphorylation. The zinc release and translocation of excitatory synapses in the hippocampus were detected, and zinc-induced tau hyperphosphorylation was also observed in cultured brain slices incubated with exogenously supplemented zinc. Tau hyperphosphorylation induced by synaptic activity was strongly associated with inactivation of protein phosphatase 2A (PP2A), and this inactivation can be reversed by pretreatment of zinc chelator. Together, these results suggest that synaptically released zinc promotes tau hyperphosphorylation through PP2A inhibition.
authors.affiliation: Department of Pathophysiology, Tongji Medical College, HuaZhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Xu-Ying
authors.initials: XY
authors.lastname: Sun
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Wei
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiong
authors.forename: Xiao-Chuan
authors.initials: XC
authors.lastname: Wang
authors.forename: Ao-Ji
authors.initials: AJ
authors.lastname: Xie
authors.forename: Xiu-Lian
authors.initials: XL
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Qun
authors.initials: Q
authors.lastname: Wang
authors.forename: You-Ming
authors.initials: YM
authors.lastname: Lu
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
authors.forename: Jian-Zhi
authors.initials: JZ
authors.lastname: Wang
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects; D015032:Zinc / Q000378:metabolism* / Q000494:pharmacology; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D016875:tau Proteins; D054648:Protein Phosphatase 2; D015032:Zinc