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Sustained imbalance in intracellular calcium (Ca²⁺) 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 Ca²⁺ handling in AD development. These studies documented physical or functional interactions of Aβ with several Ca²⁺ handling proteins located either at the plasma membrane or in intracellular organelles including the endoplasmic reticulum (ER), considered the major intracellular Ca²⁺ pool. In this review, we describe the cellular components of ER Ca²⁺ dysregulations likely responsible for AD. These include alterations of the inositol 1,4,5-trisphosphate receptors’ (IP₃Rs) and ryanodine receptors’ (RyRs) expression and function, dysfunction of the sarco-endoplasmic reticulum Ca²⁺ ATPase (SERCA) activity and upregulation of its truncated isoform (S1T), as well as presenilin (PS1, PS2)-mediated ER Ca²⁺ leak/ER Ca²⁺ release potentiation. Finally, we highlight the functional consequences of alterations of these ER Ca²⁺ components in AD pathology and unravel the potential benefit of targeting ER Ca²⁺ homeostasis as a tool to alleviate AD pathogenesis.