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 ?-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 × 10? 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.

SUBMITTER: Li X 

PROVIDER: S-EPMC6387307 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature