Abstract
To understand the role of intracellular zinc ion (Zn2+) dysregulation in mediating age-related neurodegenerative changes, particularly neurotoxicity resulting from the generation of excessive neurotoxic amyloid-β (Aβ) peptides, this study aimed to investigate whether N, N, N′, N′-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), a Zn2+-specific chelator, could attenuate Aβ25–35-induced neurotoxicity and the underlying electrophysiological mechanism. We used the 3-(4, 5-dimethyl-thiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay to measure the viability of hippocampal neurons and performed single-cell confocal imaging to detect the concentration of Zn2+ in these neurons. Furthermore, we used the whole-cell patch-clamp technique to detect the evoked repetitive action potential (APs), the voltage-gated sodium and potassium (K+) channels of primary hippocampal neurons. The analysis showed that TPEN attenuated Aβ25–35-induced neuronal death, reversed the Aβ25–35-induced increase in intracellular Zn2+ concentration and the frequency of APs, inhibited the increase in the maximum current density of voltage-activated sodium channel currents induced by Aβ25–35, relieved the Aβ25–35-induced decrease in the peak amplitude of transient outward K+ currents (IA) and outward-delayed rectifier K+ currents (IDR) at different membrane potentials, and suppressed the steady-state activation and inactivation curves of IA shifted toward the hyperpolarization direction caused by Aβ25–35. These results suggest that Aβ25–35-induced neuronal damage correlated with Zn2+ dysregulation mediated the electrophysiological changes in the voltage-gated sodium and K+ channels. Moreover, Zn2+-specific chelator-TPEN attenuated Aβ25–35-induced neuronal damage by recovering the intracellular Zn2+ concentration.
Highlights
Alzheimer’s disease (AD) is an age-related neurodegenerative disease characterized by progressive cognitive dysfunction and memory decline [1]
tetrakis (2-pyridylmethyl) ethylenediamine (TPEN) attenuates Aβ25–35‐induced hippocampal neuronal death To investigate the effect of TPEN on Aβ25–35-induced neurotoxicity, we performed a MTT assay to determine hippocampal neuronal death induced by Aβ25–35
The neuronal death induced by Aβ25–35 was markedly attenuated by treatment with TPEN in a concentration-dependent manner, it cannot be completely prevented; further, 100 nM of TPEN increased the neuronal viability to 76.98 ± 1.53%, yielding the best protective effect
Summary
Alzheimer’s disease (AD) is an age-related neurodegenerative disease characterized by progressive cognitive dysfunction and memory decline [1]. The main histopathological hallmarks of AD include extracellular senile plaques and intracellular neurofibrillary tangles [2]. Amyloid-β (Aβ) protein, the main component of senile. Aβ can trigger a deleterious cascade of events, including alterations in neuronal excitability and ion permeability, oxidative stress, inflammatory processes, cell apoptosis, and loss of synapses [4,5,6]. Z n2+ is well known for its neurotoxic effect [10]. Excess intracellular Zn2+ can stimulate the generation of reactive oxygen species in hippocampal neurons, causing oxidative stress and neuronal death [11]. Some evidence suggests that intracellular Zn2+ dysregulation may be involved in neurotoxicity caused by the generation of excessive neurotoxic
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