Fig. 7. Hypothetical molecular mechanism of enhanced Aβ production due to Ca²⁺ disruption in FAD PS cells.

APP is processed by either α-secretase or β-secretase, the latter leading to Aβ generation after subsequent cleavage by γ-secretase. Stimulation of G-protein coupled receptors (GPCR) or other cell surface receptors by extracellular ligands activates phospholipase C (PLC), which cleaves phosphatidylinositol bisphosphate (PIP₂) to produce InsP₃. InsP₃ binds to and activates the InsP₃R to release Ca²⁺ from ER stores, increasing cytoplasmic Ca²⁺ concentration. In normal cells, these Ca²⁺ signals are tightly regulated in time, space, and amplitude. In FAD cells, mutant PS exerts stimulatory effects on InsP₃R gating by modal switching to the H mode associated with prolonged channel openings. H mode gating generates exaggerated Ca²⁺ signaling by promoting additional release channel recruitment by CICR. Increased cytosolic Ca²⁺ concentration promotes β-secretase activity (52) and Aβ production (51, 54), which, together with mutant PS-enhanced production of amyloidogenic Aβ, results in plaque formation.