Alterations of the Endoplasmic Reticulum (ER) Calcium Signaling Molecular Components in Alzheimer’s Disease

Abstract

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.

Calcium Signalling in Alzheimer’s Disease: From Pathophysiological Regulation to Therapeutic Approaches

“…In this Special Issue in Cells , six reviews address the newest results and advances in calcium signalling deregulation mechanisms in AD, how they are linked to other molecular players involved in AD pathogenesis, and the potential therapeutic approaches to correct calcium alterations to treat AD [ 23 , 24 , 25 , 26 , 27 , 28 ].…”

“…In addition to synaptic plasticity deficits, calcium dyshomeostasis has a profound effect on the function of cell organelles, including ER and mitochondria, both of which play an important role in maintaining cellular and synaptic function. These specific items were discussed in our review [ 23 ] and in that by Noemi Esteras and Andrey Y. Abramov [ 25 ], respectively.…”

“…In our review [ 23 ], we describe the main neuronal calcium signalling “tool-kits” and focus on ER calcium handling molecules alterations in AD and the benefit of targeting the aforementioned to alleviate AD pathogenesis. Our review describes the tight link between the “calcium hypothesis” and the amyloidogenic cascade generating Aβ peptides and other APP-derived toxic fragments [ 30 ].…”

“…Our review describes the tight link between the “calcium hypothesis” and the amyloidogenic cascade generating Aβ peptides and other APP-derived toxic fragments [ 30 ]. ER calcium mishandling in AD includes alterations of the inositol 1,4,5-trisphosphatereceptors (IP 3 Rs) and ryanodine receptors (RyRs) expression and function, the dysfunction of the sarco-endoplasmic reticulum calcium ATPase (SERCA) activity, and the upregulation of SERCA1 truncated isoform (S1T), as well as presenilins (PS1, PS2), forming the catalytic core of the γ-secretase enzymatic complex cleaving APP [ 23 ]. We summarize the neuronal expression, structure, and physiological function for each ER molecular component.…”

“…The depletion of ER calcium content activates the store-operated calcium entry (SOCE) pathway [ 31 ]. We then report studies describing the expression and function alterations of the molecular bridge linking ER calcium depletion and the activation of plasma membrane calcium entry implicating STIM and ORAI proteins [ 23 ].…”