Ca homeostasis dysregulation in Alzheimer's disease: a focus on plasma membrane and cell organelles.

Emerging evidence indicates that Ca is a vital factor in modulating the pathogenesis of Alzheimer's disease (AD). In healthy neurons, Ca concentration is balanced to maintain a lower level in the cytosol than in the extracellular space or certain intracellular compartments such as endoplasmic reticulum (ER) and the lysosome, whereas this homeostasis is broken in AD. On the plasma membrane, the AD hallmarks amyloid-β (Aβ) and tau interact with ligand-gated or voltage-gated Ca-influx channels and inhibit the Ca-efflux ATPase or exchangers, leading to an elevated intracellular Ca level and disrupted Ca signal. In the ER, the disabled presenilin "Ca leak" function and the direct implications of Aβ and presenilin mutants contribute to Ca-signal disorder. The enhanced ryanodine receptor (RyR)-mediated and inositol 1,4,5-trisphosphate receptor (IPR)-mediated Ca release from the ER aggravates cytosolic Ca disorder and triggers apoptosis; the down-regulated ER Ca sensor, stromal interaction molecule (STIM), alleviates store-operated Ca entry in plasma membrane, leading to spine loss. The increased transfer of Ca from ER to mitochondria through mitochondria-associated ER membrane (MAM) causes Ca overload in the mitochondrial matrix and consequently opens the cellular damage-related channel, mitochondrial permeability transition pore (mPTP). In this review, we discuss the effects of Aβ, tau and presenilin on neuronal Ca signal, focusing on the receptors and regulators in plasma membrane and ER; we briefly introduce the involvement of MAM-mediated Ca transfer and mPTP opening in AD pathogenesis.-Wang, X., Zheng, W. Ca homeostasis dysregulation in Alzheimer's disease: a focus on plasma membrane and cell organelles.