Zn2+ Aggravates Tau Aggregation and Neurotoxicity

Abstract

Alzheimer′s disease (AD) is a neurodegenerative disease with high morbidity that has received extensive attention. However, its pathogenesis has not yet been completely elucidated. It is mainly related to β-amyloid protein deposition, the hyperphosphorylation of tau protein, and the loss of neurons. The main function of tau is to assemble tubulin into stable microtubules. Under pathological conditions, tau is hyperphosphorylated, which is the major component of neurofibrillary tangles (NFT) in AD. There is considerable evidence showing that the dyshomeostasis of Zn2+ is closely related to the development of AD. Herein, by using the third repeat unit of the microtubule-binding domain of tau (tau-R3), we investigated the effect of Zn2+ on the aggregation and neurotoxicity of tau. Experimental results showed that tau-R3 probably bound Zn2+ via its Cys residue with moderate affinity (association constant (Ka) = 6.82 ± 0.29 × 104 M−1). Zn2+ accelerated tau-R3 aggregation and promoted tau-R3 to form short fibrils and oligomers. Compared with tau-R3, Zn2+-tau-R3 aggregates were more toxic to Neuro-2A (N2A) cells and induced N2A cells to produce higher levels of reactive oxygen species (ROS). The dendrites and axons of Zn2+-tau-R3-treated neurons became fewer and shorter, resulting in a large number of neuronal deaths. In addition, both tau-R3 and Zn2+-tau-R3 aggregates were found to be taken up by N2A cells, and more Zn2+-tau-R3 entered the cells compared with tau-R3. Our data demonstrated that Zn2+ can aggravate tau-R3 aggregation and neurotoxicity, providing clues to understand the relationship between Zn2+ dyshomeostasis and the etiology of Alzheimer′s disease.

Molecular Mechanisms and Genetics of Oxidative Stress in Alzheimer’s Disease

“…These data suggest that the generation of tau filaments is a disulfide bond mediated process while oxidation modulates the ability to self-assemble. Consistent with this thought it was recently shown that Zn 2+ interacts with the cysteine residue of a truncated version of tau containing only the third repeat unit of the microtubule-binding domain accelerating its aggregation rate and toxicity in a Neuro-2A cell line [108]. A more direct role for oxidative stress in tau assembly was demonstrated upon administration of the anti-oxidants 2,4-disulfonyl ␣-phenyl tertiary butyl nitrone and N-acetylcysteine which reduced immunoreactivity against tau oligomers [109].…”

Mitochondria and lipid peroxidation in the mechanism of neurodegeneration: Finding ways for prevention

“…In relation to the development of neurodegenerative diseases, transition metals are involved in the formation of cytotoxic protein aggregates from misfolded proteins as shown for PD, AD, HD, and ALS 67–72 . Moreover, transition metal accumulation and metal metabolism dysfunction have been shown for postmortem brain tissue of PD and AD patients 73–75 .…”

Aggregation of biologically important peptides and proteins: inhibition or acceleration depending on protein and metal ion concentrations

“…92 Zn 2+ has also been shown to accelerate the aggregation of TP. 95 99 Huang et al (2014) studied the effects of Zn 2+ on TP in the presence and absence of Zn 2+ and the results suggest that Zn 2+ clearly causes aggregation of TP in vitro, and even the fact that removing Zn 2+ seems to remove the toxicity of TP. 96 The Zn 2+ binding site has not been clearly elucidated, though some have proposed that a cysteine residue is involved.…”