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

The pathogenesis of Alzheimer's disease (AD) is highly complex and multifactorial. Compared with A beta, 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 Zn2+ plays an important role in tau toxicity, however, the mechanism by which Zn2+ contributes to tau-induced neurotoxicity is not fully un-derstood. Our previous studies have found that Zn2+ bound 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 Zn2+ binding to R3 (Zn2++R3) significantly reduced cognitive ability and increased blood lipid and glucose levels of C57BL/6J mice. In addition, Zn2++R3, not Zn2+ or R3 alone, markedly enhanced the endogenous A beta and tau pathology and damaged the neurons of C57BL/6J mice. The study suggests that the main reason for the toxicity of Zn2+ may be the formation of Zn2+ and tau complex. Thus, preventing the combination of Zn2+ and tau may be a potential strategy for AD treatment. Furthermore, as the C57BL/6J mice injected with Zn2++R3 complex showed behavioral deficits, deposition of A beta 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.