Ca<sup>2+</sup> Dyshomeostasis Disrupts Neuronal and Synaptic Function in Alzheimer’s Disease
Ca<sup>2+</sup> homeostasis is essential for multiple neuronal functions and thus, Ca<sup>2+</sup> dyshomeostasis can lead to widespread impairment of cellular and synaptic signaling, subsequently contributing to dementia and Alzheimer’s disease (AD). While numerous studies i...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-12-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/9/12/2655 |
| _version_ | 1797545128467890176 |
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| author | John McDaid Sarah Mustaly-Kalimi Grace E. Stutzmann |
| author_facet | John McDaid Sarah Mustaly-Kalimi Grace E. Stutzmann |
| author_sort | John McDaid |
| collection | DOAJ |
| description | Ca<sup>2+</sup> homeostasis is essential for multiple neuronal functions and thus, Ca<sup>2+</sup> dyshomeostasis can lead to widespread impairment of cellular and synaptic signaling, subsequently contributing to dementia and Alzheimer’s disease (AD). While numerous studies implicate Ca<sup>2+</sup> 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 Ca<sup>2+</sup> homeostatic machinery. Ca<sup>2+</sup> homeostasis involves precise maintenance of cytosolic Ca<sup>2+</sup> levels, despite extracellular influx via multiple synaptic Ca<sup>2+</sup> channels, and intracellular release via organelles such as the endoplasmic reticulum (ER) via ryanodine receptor (RyRs) and IP<sub>3</sub>R, 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 Ca<sup>2+</sup> 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 Ca<sup>2+</sup> dyshomeostasis. Here, we detail some key findings and discuss implications for future AD treatments. |
| first_indexed | 2024-03-10T14:11:04Z |
| format | Article |
| id | doaj.art-bf07892b7a4b4c49940c7b0e40654e7f |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T14:11:04Z |
| publishDate | 2020-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-bf07892b7a4b4c49940c7b0e40654e7f2023-11-21T00:11:39ZengMDPI AGCells2073-44092020-12-01912265510.3390/cells9122655Ca<sup>2+</sup> Dyshomeostasis Disrupts Neuronal and Synaptic Function in Alzheimer’s DiseaseJohn McDaid0Sarah Mustaly-Kalimi1Grace E. Stutzmann2Center for Neurodegenerative Disease and Therapeutics, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Rd., North Chicago, IL 60064, USACenter for Neurodegenerative Disease and Therapeutics, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Rd., North Chicago, IL 60064, USACenter for Neurodegenerative Disease and Therapeutics, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Rd., North Chicago, IL 60064, USACa<sup>2+</sup> homeostasis is essential for multiple neuronal functions and thus, Ca<sup>2+</sup> dyshomeostasis can lead to widespread impairment of cellular and synaptic signaling, subsequently contributing to dementia and Alzheimer’s disease (AD). While numerous studies implicate Ca<sup>2+</sup> 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 Ca<sup>2+</sup> homeostatic machinery. Ca<sup>2+</sup> homeostasis involves precise maintenance of cytosolic Ca<sup>2+</sup> levels, despite extracellular influx via multiple synaptic Ca<sup>2+</sup> channels, and intracellular release via organelles such as the endoplasmic reticulum (ER) via ryanodine receptor (RyRs) and IP<sub>3</sub>R, 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 Ca<sup>2+</sup> 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 Ca<sup>2+</sup> dyshomeostasis. Here, we detail some key findings and discuss implications for future AD treatments.https://www.mdpi.com/2073-4409/9/12/2655calciumsynapticglutamatenicotinic receptorsmitochondriaautophagy |
| spellingShingle | John McDaid Sarah Mustaly-Kalimi Grace E. Stutzmann Ca<sup>2+</sup> Dyshomeostasis Disrupts Neuronal and Synaptic Function in Alzheimer’s Disease Cells calcium synaptic glutamate nicotinic receptors mitochondria autophagy |
| title | Ca<sup>2+</sup> Dyshomeostasis Disrupts Neuronal and Synaptic Function in Alzheimer’s Disease |
| title_full | Ca<sup>2+</sup> Dyshomeostasis Disrupts Neuronal and Synaptic Function in Alzheimer’s Disease |
| title_fullStr | Ca<sup>2+</sup> Dyshomeostasis Disrupts Neuronal and Synaptic Function in Alzheimer’s Disease |
| title_full_unstemmed | Ca<sup>2+</sup> Dyshomeostasis Disrupts Neuronal and Synaptic Function in Alzheimer’s Disease |
| title_short | Ca<sup>2+</sup> Dyshomeostasis Disrupts Neuronal and Synaptic Function in Alzheimer’s Disease |
| title_sort | ca sup 2 sup dyshomeostasis disrupts neuronal and synaptic function in alzheimer s disease |
| topic | calcium synaptic glutamate nicotinic receptors mitochondria autophagy |
| url | https://www.mdpi.com/2073-4409/9/12/2655 |
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