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Amyloid β attenuates metabotropic zinc sensing receptor, mZnR/GPR39, dependent Ca2+, ERK1/2 and Clusterin signaling in neurons

A hallmark of Alzheimer's disease is accumulation of amyloid beta (Aβ) deposits, which are associated with neuronal dysfunction, spine loss, and impaired Ca2+ homeostasis. Amyloid beta (Aβ) binds to and is aggregated by Zn2+, a metal released from synaptic glutamatergic vesicles during neuronal activity. Synaptically released Zn2+ activates a metabotropic Gq‐coupled Zn2+‐sensing receptor, mZnR/GPR39, and induces Ca2+‐signaling in post‐synaptic neurons. We examined if Aβ, as a Zn2+ binding protein, regulates neuronal Zn2+‐signaling mediated by mZnR/GPR39 using SHSY‐5Y cells and cortical neurons from GPR39 wild‐type and knockout mice. Following acute or chronic treatment with Aβ neuronal Zn2+‐dependent Ca2+ release via mZnR/GPR39 is significantly reduced. This impairment is overcome when excess Zn2+ is applied, suggesting that impaired Ca2+‐signaling results from Aβ binding of Zn2+. The Zn2+‐dependent mZnR/GPR39 activation triggers phosphorylation of extracellular regulated kinase and up‐regulates expression of the chaperone protein clusterin (Clu). Importantly, neuronal Zn2+‐dependent extracellular regulated kinase1/2 phosphorylation and up‐regulation of Clu are attenuated by silencing mZnR/GPR39 as well as by Aβ treatment. In contrast, Zn2+‐dependent AKT phosphorylation is not mediated by mZnR/GPR39 and is not attenuated by Aβ treatment. Thus, Zn2+ signaling via mZnR/GPR39 is distinctively disrupted by a critical pathological component of Alzheimer's disease.