Figure 8. AS aggregates stimulate SERCA activity leading to reduced cytosolic Ca²⁺ and neuron dysfunction and death.

AS aggregates bind and stimulate the active SERCA‐mediated transport of cytosolic Ca²⁺ into the endoplasmic reticulum. During the building‐up process of cytosolic AS aggregates, the stimulation of SERCA causes an early reduction in cytosolic Ca²⁺, increased ER Ca²⁺ that could lead to increased mitochondrial Ca²⁺. The dysregulated Ca²⁺ perturbs Ca²⁺‐dependent processes, leading to progressive neuronal dysfunctions. Ultimately, compensatory mechanisms fail, whereafter cytosolic Ca²⁺ rise and the neurons die. Inhibition of AS aggregation by the inhibitor ASI‐1D and reducing the activity of SERCA by its inhibitor CPA counteracts the Ca²⁺ dysregulation and protect the neurons.