Ca2+ homeostasis dysregulation in Alzheimer's disease: a focus on plasma membrane and cell organelles

Abstract

Emerging evidence indicates that Ca²⁺ is a vital factor in modulating the pathogenesis of Alzheimer's disease (AD). In healthy neurons, Ca²⁺ 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 Ca²⁺-influx channels and inhibit the Ca²⁺-efflux ATPase or exchangers, leading to an elevated intracellular Ca²⁺ level and disrupted Ca²⁺ signal. In the ER, the disabled presenilin "Ca²⁺ leak" function and the direct implications of Aβ and presenilin mutants contribute to Ca²⁺-signal disorder. The enhanced ryanodine receptor (RyR)-mediated and inositol 1,4,5-trisphosphate receptor (IP₃R)-mediated Ca²⁺ release from the ER aggravates cytosolic Ca²⁺ disorder and triggers apoptosis; the down-regulated ER Ca²⁺ sensor, stromal interaction molecule (STIM), alleviates store-operated Ca²⁺ entry in plasma membrane, leading to spine loss. The increased transfer of Ca²⁺ from ER to mitochondria through mitochondria-associated ER membrane (MAM) causes Ca²⁺ 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 Ca²⁺ signal, focusing on the receptors and regulators in plasma membrane and ER; we briefly introduce the involvement of MAM-mediated Ca²⁺ transfer and mPTP opening in AD pathogenesis.-Wang, X., Zheng, W. Ca²⁺ homeostasis dysregulation in Alzheimer's disease: a focus on plasma membrane and cell organelles.

Keywords: AD; Ca channel; MAM; endoplasmic reticulum; mPTP.