Lead induced intracellular copper redox imbalance with aggravated cellular dysfunction

Area of Science:

• Neuroscience
• Environmental Health
• Toxicology
• Cell Biology

Background:

• Lead (Pb) is a neurotoxicant, but its effects on copper (Cu) redox states and cellular dysfunction are unclear.
• Copper's redox equilibrium is vital for mitochondrial function, essential for neuronal health.
• Alzheimer's disease (AD) involves complex cellular pathologies potentially influenced by environmental factors.

Purpose of the Study:

• To investigate the impact of lead toxicity on copper redox dynamics in human neuron cells.
• To explore lead's role in Alzheimer's disease-like pathogenesis using a cellular model.
• To elucidate the mechanisms of lead-induced neurotoxicity and its interaction with copper homeostasis.

Main Methods:

• Utilized SH-SY5Y cells as a normal human neuron model and an Alzheimer's disease (AD) cell model.
• Imaged subcellular localization of Cu(II) and Cu(I) to assess copper redox states.
• Performed proteomic analysis to identify protein expression changes in response to lead exposure.

Main Results:

• Lead exposure oxidized Cu(I) to Cu(II), leading to abnormal Cu(II) accumulation in mitochondria and lysosomes.
• Disrupted copper homeostasis resulted in mitochondrial dysfunction, increased oxidative stress, and impaired cellular integrity.
• Proteomic analysis revealed dysregulation of proteins involved in copper homeostasis and upregulation of AD-associated proteins (e.g., APP).

Conclusions:

• Lead induces intracellular copper redox imbalance by promoting Cu(I) oxidation to Cu(II), aggravating Alzheimer's disease pathogenesis.
• Mitochondrial damage plays a central role in lead-induced cytotoxicity in both normal and AD-like neuronal models.
• This study provides critical insights into the molecular mechanisms underlying lead neurotoxicity and its exacerbation of AD.