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 (A beta) deposits, which are associated with neuronal dysfunction, spine loss, and impaired Ca2+ homeostasis. Amyloid beta (A beta) 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 A beta, 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 A beta 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 A beta 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 A beta treatment. In contrast, Zn2+-dependent AKT phosphorylation is not mediated by mZnR/GPR39 and is not attenuated by A beta treatment. Thus, Zn2+ signaling via mZnR/GPR39 is distinctively disrupted by a critical pathological component of Alzheimer's disease.