Figure 1. Calcium dysregulation in Alzheimer disease.

Sequential cleavages of β-amyloid precursor protein (APP) by β-secretase (β) and β-secretase (β) generate amyloid β peptide (Aβ). Aβ forms oligomers, which can insert into the plasma membrane and form Ca²⁺-permeable pores. The association of Aβ oligomers with the plasma membrane is facilitated by binding to surface phosphatidylserine (PtdS); age and Ca²⁺-related mitochondrial impairment leads to ATP depletion and might trigger flipping of PtdS from the inner portion of the plasma membrane to the cell surface. Reduction in ATP levels and loss of membrane integrity causes membrane depolarization, which leads to facilitation of Ca²⁺ influx through NMDAR and VGCC. Aβ oligomers can also affect activity of NMDAR, AMPAR and VGCC directly. Glutamate stimulates activation of mGluR1/5 receptors, production of InsP3 and InsP3R -mediated Ca²⁺ release from the ER. Presenilins (PS) function as an ER Ca²⁺-leak channels and many FAD mutations impair Ca²⁺-leak-channel function of PS, resulting in excessive accumulation of Ca²⁺ in the ER. Increased ER Ca²⁺ levels result in enhanced Ca²⁺ release through InsP3 -gated InsP3R 1 and Ca²⁺-gated RyanR(2/3). PS might also modulate activity of InsP3R, RyanR and SERCA pump directly. The activity of store-operated Ca²⁺ channels on the plasma membrane can be affected indirectly by PS mutations through the modulation of SERCA activity. Elevated cytosolic Ca²⁺ levels result in the activation of calcineurin (CaN) and calpains and lead to facilitation of LTD, inhibition of LTP, modification of neuronal cytoskeleton, synaptic loss and neuritic atrophy. Excessive Ca²⁺ is taken up by mitochondria through mitochondrial Ca²⁺ uniporter (MCU), eventually leading to opening of mitochondrial permeability-transition pore (mtPTP) and apoptosis.