Abstract
Sustained imbalance in intracellular calcium (Ca(2+)) entry and clearance alters cellular integrity, ultimately leading to cellular homeostasis disequilibrium and cell death. Alzheimer's disease (AD) is the most common cause of dementia. Beside the major pathological features associated with AD-linked toxic amyloid beta (Aβ) and hyperphosphorylated tau (p-tau), several studies suggested the contribution of altered Ca(2+) handling in AD development. These studies documented physical or functional interactions of Aβ with several Ca(2+) handling proteins located either at the plasma membrane or in intracellular organelles including the endoplasmic reticulum (ER), considered the major intracellular Ca(2+) pool. In this review, we describe the cellular components of ER Ca(2+) dysregulations likely responsible for AD. These include alterations of the inositol 1,4,5-trisphosphate receptors' (IP(3)Rs) and ryanodine receptors' (RyRs) expression and function, dysfunction of the sarco-endoplasmic reticulum Ca(2+) ATPase (SERCA) activity and upregulation of its truncated isoform (S1T), as well as presenilin (PS1, PS2)-mediated ER Ca(2+) leak/ER Ca(2+) release potentiation. Finally, we highlight the functional consequences of alterations of these ER Ca(2+) components in AD pathology and unravel the potential benefit of targeting ER Ca(2+) homeostasis as a tool to alleviate AD pathogenesis.