Ca2+ dysregulation in the endoplasmic reticulum related to Alzheimer's disease: a review on experimental progress and computational modeling

Abstract

Alzheimer's disease (AD) is a devastating, incurable neurodegenerative disease affecting millions of people worldwide. Dysregulation of intracellular Ca²⁺ signaling has been observed as an early event prior to the presence of clinical symptoms of AD and is believed to be a crucial factor contributing to its pathogenesis. The progressive and sustaining increase in the resting level of cytosolic Ca²⁺ will affect downstream activities and neural functions. This review focuses on the issues relating to the increasing Ca²⁺ release from the endoplasmic reticulum (ER) observed in AD neurons. Numerous research papers have suggested that the dysregulation of ER Ca²⁺ homeostasis is associated with mutations in the presenilin genes and amyloid-β oligomers. These disturbances could happen at many different points in the signaling process, directly affecting ER Ca²⁺ channels or interfering with related pathways, which makes it harder to reveal the underlying mechanisms. This review paper also shows that computational modeling is a powerful tool in Ca²⁺ signaling studies and discusses the progress in modeling related to Ca²⁺ dysregulation in AD research.