Figure 5. Potential interplay between Aβ oligomers, Ca²⁺, and a target cell in the initial stages of Alzheimer's disease.

(1) Age-related increase in [Ca²⁺]_i promotes oligomerization of intracellular Aβ. (2) Disruption of Ca²⁺ homeostasis by oligomers, by either binding to or modulating the activity of a number of receptors such as ryanodine (Ry) and inositol triphosphate (IP₃R) [25]. (3) Increase in [Ca²⁺]_i. These three steps might form an inimical cycle leading to increases in both cytosolic calcium and Aβ oligomer concentrations. (4) Aβ oligomers disrupt intracellular membranes, leading to apoptosis [34], [41], [64]. (5) Extracellular calcium concentration ([Ca²⁺]_e) promotes oligomerization of extracellular Aβ. (6) Oligomers form nonspecific pores in the plasma membrane, disturbing cellular integrity and leading to apoptosis [65]. (7) Aβ oligomers can interact and impair calcium channels at the membrane surface, opening calcium importers and blocking calcium exporters such as the voltage-dependent calcium channel [66]. Aβ oligomers can affect surface expression of N-methyl-D-aspartate receptors (NMDARs) [67], may increase [68] or decrease the conductance [69], and facilitate long-term synaptic depression by disrupting neuronal glutamate uptake [70].