Zinc exacerbates tau-induced Alzheimer-like pathology in C57BL/6J mice.

Abstract

The pathogenesis of Alzheimer's disease (AD) is highly complex and multifactorial. Compared with Aβ, the pathological changes associated with tau are more related to the clinical symptoms and more indicative of the severity of AD. Studies have shown that the direct interaction between tau and Znplays an important role in tau toxicity, however, the mechanism by which Zncontributes to tau-induced neurotoxicity is not fully understood. Our previous studies have found that Znbound to the third repeat unit of the microtubule-binding domain of tau (R3) with moderate affinity and induced R3 to form oligomers, thus increased the toxicity of R3 to nerve cells. Here, we demonstrated that Znbinding to R3 (Zn+R3) significantly reduced cognitive ability and increased blood lipid and glucose levels of C57BL/6J mice. In addition, Zn+R3, not Znor R3 alone, markedly enhanced the endogenous Aβ and tau pathology and damaged the neurons of C57BL/6J mice. The study suggests that the main reason for the toxicity of Znmay be the formation of Znand tau complex. Thus, preventing the combination of Znand tau may be a potential strategy for AD treatment. Furthermore, as the C57BL/6J mice injected with Zn+R3 complex showed behavioral deficits, deposition of Aβ plaques and tau tangles, and the death of neurons within 45 days. Thus, they can be considered as a fast sporadic AD or other tauopathies mouse model.