Zinc Exacerbates Tau-Induced Neuronal Damage and Autophagy Dysfunction by Inhibiting the Akt/mTOR Pathway

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder in which tau pathology correlates more strongly with clinical progression than amyloid-β (Aβ). Zinc (Zn²⁺) is known to promote tau-mediated neurotoxicity; however, the underlying mechanisms remain incompletely understood. Our previous work demonstrated that Zinc ions (Zn²⁺) binds to the third microtubule-binding repeat (R3) of tau, inducing oligomerization and enhancing neurotoxicity. Here, we demonstrated that Zn²⁺+R3 elevated phosphorylated tau (p-tau) levels, impaired dendritic spine morphology, reduced synaptophysin expression, and disrupted autophagic flux. Mechanistically, Zn²⁺+R3 was associated with suppression of the Akt/mTOR signaling pathway, concurrent with autophagy initiation and impaired autophagosome-lysosome fusion. However, the present findings are associative in nature, as pharmacological or genetic rescue experiments were not performed; such experiments will be required to formally establish causality. Collectively, these findings suggest that targeting the Zn²⁺ and R3 interaction may represent a potential therapeutic strategy for AD.