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.
Highlights
Occurs through activation of the inositol 1,4,5-trisphosphate receptors (IP3 R) downstream of metabotropic receptors (Figure 1), or through the activation of ryanodine receptors (RyRs) that are activated by a slight increase in [Ca2+ ]cyt, a mechanism known as Ca2+ -induced Ca2+ release (CICR) (Figure 1)
We previously demonstrated that the human SERCA1 truncated isoform (S1T) [217] is induced under pharmacological and physiopathological endoplasmic reticulum (ER) stress through the activation of the PERK-eIF2α-ATF4-CHOP pathway [218]
Recent studies demonstrated that the failure of the store-operated Ca2+ entry (SOCE) molecular bridge between the ER and the plasma membrane has to be seriously considered as a major molecular mechanism controlling ER Ca2+ content and ER-mediated Ca2+
Summary
As a signal transduction molecule, calcium (Ca2+ ) regulates a large number of neuronal processes including growth and differentiation, neurotransmitter release and synaptic function, activity-dependent changes in gene expression and apoptosis [1]. Cytosolic Ca2+ ([Ca2+ ]cyt) signals are regulated in a spatiotemporal-dependent manner underlined by an intricate interplay between Ca2+ entry through the plasma membrane, storage in the internal stores (i.e., the endoplasmic reticulum (ER), considered the major dynamic Ca2+ intracellular pool), Ca2+ mobilization from the ER and its buffering by Ca2+ -binding proteins (CaBP) (Figure 1). Ca2+ entry through the plasma membrane occurs through ligand-dependent. Ca2+ mobilization from the ER occurs through activation of the inositol 1,4,5-trisphosphate receptors (IP3 R) downstream of metabotropic receptors (Figure 1), or through the activation of ryanodine receptors (RyRs) that are activated by a slight increase in [Ca2+ ]cyt, a mechanism known as Ca2+ -induced Ca2+ release (CICR) (Figure 1). Several lines of evidence indicate that Ca2+ homeostasis could be disrupted upon cellular challenges as well as in neurodegenerative conditions
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