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. (Figure presented.) Synaptically released Zn²⁺ activates a Zn²⁺-sensing receptor, mZnR/GPR39, and induces Ca²⁺-signaling, followed by ERK1/2 MAPK activation and up-regulation of clusterin. Amyloid beta (Aβ) binds to Zn²⁺ thus forming oligomers that are a hallmark of Alzheimer's disease. We show that Aβ attenuates Zn²⁺-dependent Ca²⁺-responses, abolishes ERK1/2 activation and down-regulates clusterin expression. Thus, Zn²⁺ signaling via mZnR/GPR39 is disrupted by Aβ, a critical pathological component of Alzheimer's disease.