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

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 29939

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Mounia Chami

E-Mail Website
Guest Editor
Laboratory of excellence DistALZ, Université Côte d’Azur, INSERM, CNRS, IPMC, 660 route des Lucioles, 06560 Sophia-Antipolis, Valbonne, France
Interests: mitochondria; mitophagy; endoplasmic reticulum stress; calcium signaling; Alzheimer’s disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Alzheimer’s disease (AD) is the most commonly known neurodegenerative disorder, causing dementia. AD is a proteinopathy characterized by the accumulation of extracellular amyloid beta aggregates and intracellular hyperphosphorylated Tau protein contributing to neuronal dysfunction and demise. Cellular calcium signaling regulates several facets of neuronal physiology orchestrating cell life and death mechanisms and most key events in between. In recent decades, several studies have reported calcium dysregulation in AD, affecting different cellular compartments, such as mitochondria, endoplasmic reticulum, lysosomes, and several microdomains within the plasma membrane, and occurring through a broad intervention of several calcium signaling “tool-kits” (receptors, channels, binding proteins, etc.). The obtained results depict calcium signaling dysregulation as a common proximal cause of dysfunctional neurons and also glial supporting cells. The objective of this Special Issue is to gather the newest results and advances on: i) calcium signaling deregulation mechanisms in AD, ii) how they are linked to other players involved in AD pathogenesis, and iii) potential therapeutic approaches to correct calcium alterations to treat AD.

Dr. Mounia Chami
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Alzheimer’s disease
  • aging
  • amyloid β
  • amyloid precursor protein
  • calcium
  • Ca2+ signaling
  • Ca2+ channels
  • Ca2+ receptors
  • Ca2+ binding proteins
  • endoplasmic reticulum
  • mitochondria
  • lysosomes
  • synaptic plasticity
  • IP3R
  • RyR
  • SOCE
  • presennilin
  • glutamate receptors
  • AMPA receptors
  • neurons
  • astrocytes
  • microglia
  • neurodegeneration

Published Papers (7 papers)

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Editorial

Jump to: Review

4 pages, 222 KiB  
Editorial
Calcium Signalling in Alzheimer’s Disease: From Pathophysiological Regulation to Therapeutic Approaches
by Mounia Chami
Cells 2021, 10(1), 140; https://doi.org/10.3390/cells10010140 - 12 Jan 2021
Cited by 7 | Viewed by 2183
Abstract
Alzheimer’s disease (AD) is a neurodegenerative pathology representing a socioeconomic challenge, however, the complex mechanism behind the disease is not yet fully understood [...] Full article
(This article belongs to the Special Issue Calcium Signalling in Alzheimer’s Disease: From Pathophysiological Regulation to Therapeutic Approaches)

Review

Jump to: Editorial

25 pages, 2579 KiB  
Review
Ca2+ Dyshomeostasis Disrupts Neuronal and Synaptic Function in Alzheimer’s Disease
by John McDaid, Sarah Mustaly-Kalimi and Grace E. Stutzmann
Cells 2020, 9(12), 2655; https://doi.org/10.3390/cells9122655 - 10 Dec 2020
Cited by 33 | Viewed by 4442
Abstract
Ca2+ homeostasis is essential for multiple neuronal functions and thus, Ca2+ dyshomeostasis can lead to widespread impairment of cellular and synaptic signaling, subsequently contributing to dementia and Alzheimer’s disease (AD). While numerous studies implicate Ca2+ mishandling in AD, the cellular [...] Read more.
Ca2+ homeostasis is essential for multiple neuronal functions and thus, Ca2+ dyshomeostasis can lead to widespread impairment of cellular and synaptic signaling, subsequently contributing to dementia and Alzheimer’s disease (AD). While numerous studies implicate Ca2+ mishandling in AD, the cellular basis for loss of cognitive function remains under investigation. The process of synaptic degradation and degeneration in AD is slow, and constitutes a series of maladaptive processes each contributing to a further destabilization of the Ca2+ homeostatic machinery. Ca2+ homeostasis involves precise maintenance of cytosolic Ca2+ levels, despite extracellular influx via multiple synaptic Ca2+ channels, and intracellular release via organelles such as the endoplasmic reticulum (ER) via ryanodine receptor (RyRs) and IP3R, lysosomes via transient receptor potential mucolipin channel (TRPML) and two pore channel (TPC), and mitochondria via the permeability transition pore (PTP). Furthermore, functioning of these organelles relies upon regulated inter-organelle Ca2+ handling, with aberrant signaling resulting in synaptic dysfunction, protein mishandling, oxidative stress and defective bioenergetics, among other consequences consistent with AD. With few effective treatments currently available to mitigate AD, the past few years have seen a significant increase in the study of synaptic and cellular mechanisms as drivers of AD, including Ca2+ dyshomeostasis. Here, we detail some key findings and discuss implications for future AD treatments. Full article
(This article belongs to the Special Issue Calcium Signalling in Alzheimer’s Disease: From Pathophysiological Regulation to Therapeutic Approaches)
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23 pages, 1670 KiB  
Review
Alterations of the Endoplasmic Reticulum (ER) Calcium Signaling Molecular Components in Alzheimer’s Disease
by Mounia Chami and Frédéric Checler
Cells 2020, 9(12), 2577; https://doi.org/10.3390/cells9122577 - 01 Dec 2020
Cited by 32 | Viewed by 5391
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Calcium Signalling in Alzheimer’s Disease: From Pathophysiological Regulation to Therapeutic Approaches)
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29 pages, 1435 KiB  
Review
Therapeutic Strategies to Target Calcium Dysregulation in Alzheimer’s Disease
by Maria Calvo-Rodriguez, Elizabeth K. Kharitonova and Brian J. Bacskai
Cells 2020, 9(11), 2513; https://doi.org/10.3390/cells9112513 - 20 Nov 2020
Cited by 23 | Viewed by 4761
Abstract
Alzheimer’s disease (AD) is the most common form of dementia, affecting millions of people worldwide. Unfortunately, none of the current treatments are effective at improving cognitive function in AD patients and, therefore, there is an urgent need for the development of new therapies [...] Read more.
Alzheimer’s disease (AD) is the most common form of dementia, affecting millions of people worldwide. Unfortunately, none of the current treatments are effective at improving cognitive function in AD patients and, therefore, there is an urgent need for the development of new therapies that target the early cause(s) of AD. Intracellular calcium (Ca2+) regulation is critical for proper cellular and neuronal function. It has been suggested that Ca2+ dyshomeostasis is an upstream factor of many neurodegenerative diseases, including AD. For this reason, chemical agents or small molecules aimed at targeting or correcting this Ca2+ dysregulation might serve as therapeutic strategies to prevent the development of AD. Moreover, neurons are not alone in exhibiting Ca2+ dyshomeostasis, since Ca2+ disruption is observed in other cell types in the brain in AD. In this review, we examine the distinct Ca2+ channels and compartments involved in the disease mechanisms that could be potential targets in AD. Full article
(This article belongs to the Special Issue Calcium Signalling in Alzheimer’s Disease: From Pathophysiological Regulation to Therapeutic Approaches)
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27 pages, 3439 KiB  
Review
Potential Drug Candidates to Treat TRPC6 Channel Deficiencies in the Pathophysiology of Alzheimer’s Disease and Brain Ischemia
by Veronika Prikhodko, Daria Chernyuk, Yurii Sysoev, Nikita Zernov, Sergey Okovityi and Elena Popugaeva
Cells 2020, 9(11), 2351; https://doi.org/10.3390/cells9112351 - 24 Oct 2020
Cited by 14 | Viewed by 3192
Abstract
Alzheimer’s disease and cerebral ischemia are among the many causative neurodegenerative diseases that lead to disabilities in the middle-aged and elderly population. There are no effective disease-preventing therapies for these pathologies. Recent in vitro and in vivo studies have revealed the TRPC6 channel [...] Read more.
Alzheimer’s disease and cerebral ischemia are among the many causative neurodegenerative diseases that lead to disabilities in the middle-aged and elderly population. There are no effective disease-preventing therapies for these pathologies. Recent in vitro and in vivo studies have revealed the TRPC6 channel to be a promising molecular target for the development of neuroprotective agents. TRPC6 channel is a non-selective cation plasma membrane channel that is permeable to Ca2+. Its Ca2+-dependent pharmacological effect is associated with the stabilization and protection of excitatory synapses. Downregulation as well as upregulation of TRPC6 channel functions have been observed in Alzheimer’s disease and brain ischemia models. Thus, in order to protect neurons from Alzheimer’s disease and cerebral ischemia, proper TRPC6 channels modulators have to be used. TRPC6 channels modulators are an emerging research field. New chemical structures modulating the activity of TRPC6 channels are being currently discovered. The recent publication of the cryo-EM structure of TRPC6 channels should speed up the discovery process even more. This review summarizes the currently available information about potential drug candidates that may be used as basic structures to develop selective, highly potent TRPC6 channel modulators to treat neurodegenerative disorders, such as Alzheimer’s disease and cerebral ischemia. Full article
(This article belongs to the Special Issue Calcium Signalling in Alzheimer’s Disease: From Pathophysiological Regulation to Therapeutic Approaches)
20 pages, 1737 KiB  
Review
Presenilin-2 and Calcium Handling: Molecules, Organelles, Cells and Brain Networks
by Paola Pizzo, Emy Basso, Riccardo Filadi, Elisa Greotti, Alessandro Leparulo, Diana Pendin, Nelly Redolfi, Michela Rossini, Nicola Vajente, Tullio Pozzan and Cristina Fasolato
Cells 2020, 9(10), 2166; https://doi.org/10.3390/cells9102166 - 25 Sep 2020
Cited by 21 | Viewed by 3477
Abstract
Presenilin-2 (PS2) is one of the three proteins that are dominantly mutated in familial Alzheimer’s disease (FAD). It forms the catalytic core of the γ-secretase complex—a function shared with its homolog presenilin-1 (PS1)—the enzyme ultimately responsible of amyloid-β (Aβ) formation. Besides its enzymatic [...] Read more.
Presenilin-2 (PS2) is one of the three proteins that are dominantly mutated in familial Alzheimer’s disease (FAD). It forms the catalytic core of the γ-secretase complex—a function shared with its homolog presenilin-1 (PS1)—the enzyme ultimately responsible of amyloid-β (Aβ) formation. Besides its enzymatic activity, PS2 is a multifunctional protein, being specifically involved, independently of γ-secretase activity, in the modulation of several cellular processes, such as Ca2+ signalling, mitochondrial function, inter-organelle communication, and autophagy. As for the former, evidence has accumulated that supports the involvement of PS2 at different levels, ranging from organelle Ca2+ handling to Ca2+ entry through plasma membrane channels. Thus FAD-linked PS2 mutations impact on multiple aspects of cell and tissue physiology, including bioenergetics and brain network excitability. In this contribution, we summarize the main findings on PS2, primarily as a modulator of Ca2+ homeostasis, with particular emphasis on the role of its mutations in the pathogenesis of FAD. Identification of cell pathways and molecules that are specifically targeted by PS2 mutants, as well as of common targets shared with PS1 mutants, will be fundamental to disentangle the complexity of memory loss and brain degeneration that occurs in Alzheimer’s disease (AD). Full article
(This article belongs to the Special Issue Calcium Signalling in Alzheimer’s Disease: From Pathophysiological Regulation to Therapeutic Approaches)
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17 pages, 1436 KiB  
Review
Mitochondrial Calcium Deregulation in the Mechanism of Beta-Amyloid and Tau Pathology
by Noemi Esteras and Andrey Y. Abramov
Cells 2020, 9(9), 2135; https://doi.org/10.3390/cells9092135 - 21 Sep 2020
Cited by 62 | Viewed by 5725
Abstract
Aggregation and deposition of β-amyloid and/or tau protein are the key neuropathological features in neurodegenerative disorders such as Alzheimer’s disease (AD) and other tauopathies including frontotemporal dementia (FTD). The interaction between oxidative stress, mitochondrial dysfunction and the impairment of calcium ions (Ca2+ [...] Read more.
Aggregation and deposition of β-amyloid and/or tau protein are the key neuropathological features in neurodegenerative disorders such as Alzheimer’s disease (AD) and other tauopathies including frontotemporal dementia (FTD). The interaction between oxidative stress, mitochondrial dysfunction and the impairment of calcium ions (Ca2+) homeostasis induced by misfolded tau and β-amyloid plays an important role in the progressive neuronal loss occurring in specific areas of the brain. In addition to the control of bioenergetics and ROS production, mitochondria are fine regulators of the cytosolic Ca2+ homeostasis that induce vital signalling mechanisms in excitable cells such as neurons. Impairment in the mitochondrial Ca2+ uptake through the mitochondrial Ca2+ uniporter (MCU) or release through the Na+/Ca2+ exchanger may lead to mitochondrial Ca2+ overload and opening of the permeability transition pore inducing neuronal death. Recent evidence suggests an important role for these mechanisms as the underlying causes for neuronal death in β-amyloid and tau pathology. The present review will focus on the mechanisms that lead to cytosolic and especially mitochondrial Ca2+ disturbances occurring in AD and tau-induced FTD, and propose possible therapeutic interventions for these disorders. Full article
(This article belongs to the Special Issue Calcium Signalling in Alzheimer’s Disease: From Pathophysiological Regulation to Therapeutic Approaches)
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