The Role of Mitochondrial Calcium Homeostasis in Alzheimer’s and Related Diseases

Ryan, Kerry C.; Ashkavand, Zahra; Norman, Kenneth R.

doi:10.3390/ijms21239153

Cited by 59 publications

(48 citation statements)

References 158 publications

(198 reference statements)

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“…Many aspects of mitochondrial dysfunction have been observed in neurodegenerative conditions: change in their size and number, abnormal mitochondrial dynamics, reduced energy metabolism, reduced expression and activity of key enzymes of oxidative metabolism, increased rate of mutations in mitochondrial DNA (mtDNA), increased vulnerability to ROS attack and activation of intrinsic apoptotic pathway components (although not necessarily leading to apoptosis) [7,21,34,35]. OS-induced endoplasmic reticulum (ER) stress, calcium overload and disturbance of mitochondrial calcium homeostasis further contribute to mitochondrial failure and disease progression [7,[36][37][38].…”

Section: Oxidative Stress In Neurodegenerative Diseases: the Role Of Nrf2 Pathwaymentioning

confidence: 99%

Anti-Oxidative, Anti-Inflammatory and Anti-Apoptotic Effects of Flavonols: Targeting Nrf2, NF-κB and p53 Pathways in Neurodegeneration

et al. 2021

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Neurodegenerative diseases are one of the leading causes of disability and death worldwide. Intracellular transduction pathways that end in the activation of specific transcription factors are highly implicated in the onset and progression of pathological changes related to neurodegeneration, of which those related to oxidative stress (OS) and neuroinflammation are particularly important. Here, we provide a brief overview of the key concepts related to OS- and neuroinflammation-mediated neuropathological changes in neurodegeneration, together with the role of transcription factors nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor-κB (NF-κB). This review is focused on the transcription factor p53 that coordinates the cellular response to diverse genotoxic stimuli, determining neuronal death or survival. As current pharmacological options in the treatment of neurodegenerative disease are only symptomatic, many research efforts are aimed at uncovering efficient disease-modifying agents. Natural polyphenolic compounds demonstrate powerful anti-oxidative, anti-inflammatory and anti-apoptotic effects, partially acting as modulators of signaling pathways. Herein, we review the current understanding of the therapeutic potential and limitations of flavonols in neuroprotection, with emphasis on their anti-oxidative, anti-inflammatory and anti-apoptotic effects along the Nrf2, NF-κB and p53 pathways. A better understanding of cellular and molecular mechanisms of their action may pave the way toward new treatments.

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Section: Oxidative Stress In Neurodegenerative Diseases: the Role Of Nrf2 Pathwaymentioning

confidence: 99%

Anti-Oxidative, Anti-Inflammatory and Anti-Apoptotic Effects of Flavonols: Targeting Nrf2, NF-κB and p53 Pathways in Neurodegeneration

et al. 2021

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“…Indeed, this is an effect of exogenous Aβ peptides that has been experimentally demonstrated [ 150 , 151 ]. Cumulative lines of evidence have demonstrated that mitochondrial Ca 2+ signaling is altered in AD due to mutations in the PSEN proteins [ 152 , 153 ]. The excess in cytosolic Ca 2+ caused by enhanced ER Ca 2+ release caused by mutant PSENs is, at least in part, counterbalanced by the Ca 2+ uptake through the voltage-dependent anion-selective channel protein and the calcium uniporter of the mitochondria.…”

Section: Modulation By Aβ Of Cambps Which Play Major Roles In Aβ Production In Neuronal Calcium Homeostasis and Ltpmentioning

confidence: 99%

“…A sustained increase in mitochondrial Ca 2+ concentration impairs ATP production, increases reactive oxygen species (ROS) production, and the opening of the mitochondrial permeability transition pore [ 154 ]. Several studies have proposed that enhanced neuronal apoptosis and increased ROS production are major factors in the neurodegeneration observed in AD, and the accumulation of mitochondrial Ca 2+ has been shown to be significantly implicated in these neurotoxic pathways [ 153 , 154 ]. Upregulation of genes related to mitochondrial energy metabolism and apoptosis has been already reported in an AD transgenic mouse model overexpressing a mutant form of APP at different stages of AD progression [ 155 ].…”

Section: Modulation By Aβ Of Cambps Which Play Major Roles In Aβ Production In Neuronal Calcium Homeostasis and Ltpmentioning

confidence: 99%

“…Since these authors observed the same upregulation in MAM function and ER mitochondrial communication in fibroblasts from patients with sAD, without mutations in PSEN1, PSEN2, and APP, they suggested that MAM-upregulated function is a common feature in both fAD and sAD, and proposed that it may represent a pathogenic initiator of AD [ 160 , 161 ]. In addition, other recent studies have shown that an increase in Aβ production may perturb mitochondria and mitochondria–ER contact site functions, mediating the neurodegeneration observed in AD, see, e.g., [ 153 , 162 ].…”

Section: Modulation By Aβ Of Cambps Which Play Major Roles In Aβ Production In Neuronal Calcium Homeostasis and Ltpmentioning

confidence: 99%

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The Relevance of Amyloid β-Calmodulin Complexation in Neurons and Brain Degeneration in Alzheimer’s Disease

Poejo

Salazar

Mata

et al. 2021

IJMS

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Intraneuronal amyloid β (Aβ) oligomer accumulation precedes the appearance of amyloid plaques or neurofibrillary tangles and is neurotoxic. In Alzheimer’s disease (AD)-affected brains, intraneuronal Aβ oligomers can derive from Aβ peptide production within the neuron and, also, from vicinal neurons or reactive glial cells. Calcium homeostasis dysregulation and neuronal excitability alterations are widely accepted to play a key role in Aβ neurotoxicity in AD. However, the identification of primary Aβ-target proteins, in which functional impairment initiating cytosolic calcium homeostasis dysregulation and the critical point of no return are still pending issues. The micromolar concentration of calmodulin (CaM) in neurons and its high affinity for neurotoxic Aβ peptides (dissociation constant ≈ 1 nM) highlight a novel function of CaM, i.e., the buffering of free Aβ concentrations in the low nanomolar range. In turn, the concentration of Aβ-CaM complexes within neurons will increase as a function of time after the induction of Aβ production, and free Aβ will rise sharply when accumulated Aβ exceeds all available CaM. Thus, Aβ-CaM complexation could also play a major role in neuronal calcium signaling mediated by calmodulin-binding proteins by Aβ; a point that has been overlooked until now. In this review, we address the implications of Aβ-CaM complexation in the formation of neurotoxic Aβ oligomers, in the alteration of intracellular calcium homeostasis induced by Aβ, and of dysregulation of the calcium-dependent neuronal activity and excitability induced by Aβ.

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“…Based on the multifactorial aspect of AD, it is more likely that pleiotropic mechanisms interfere with each other or exist side by side, finally leading to pathological changes. For example, Aβ has been shown in cell culture and animal models to enhance cytoplasmic calcium levels, and elevated calcium, in turn, interferes with mitochondrial function, reducing ATP production [14][15][16][17]. Decreased energy or ATP level are a common characteristic of AD [18,19].…”

Section: Introductionmentioning

confidence: 99%

Targeted Lipidomics of Mitochondria in a Cellular Alzheimer’s Disease Model

et al. 2021

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Alzheimer’s disease (AD) is neuropathologically characterized by the accumulation of Amyloid-β (Aβ) in senile plaques derived from amyloidogenic processing of a precursor protein (APP). Recently, changes in mitochondrial function have become in the focus of the disease. Whereas a link between AD and lipid-homeostasis exists, little is known about potential alterations in the lipid composition of mitochondria. Here, we investigate potential changes in the main mitochondrial phospholipid classes phosphatidylcholine, phosphatidylethanolamine and the corresponding plasmalogens and lyso-phospholipids of a cellular AD-model (SH-SY5Y APPswedish transfected cells), comparing these results with changes in cell-homogenates. Targeted shotgun-lipidomics revealed lipid alterations to be specific for mitochondria and cannot be predicted from total cell analysis. In particular, lipids containing three and four times unsaturated fatty acids (FA X:4), such as arachidonic-acid, are increased, whereas FA X:6 or X:5, such as eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), are decreased. Additionally, PE plasmalogens are increased in contrast to homogenates. Results were confirmed in another cellular AD model, having a lower affinity to amyloidogenic APP processing. Besides several similarities, differences in particular in PE species exist, demonstrating that differences in APP processing might lead to specific changes in lipid homeostasis in mitochondria. Importantly, the observed lipid alterations are accompanied by changes in the carnitine carrier system, also suggesting an altered mitochondrial functionality.

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The Role of Mitochondrial Calcium Homeostasis in Alzheimer’s and Related Diseases

Cited by 59 publications

References 158 publications

Anti-Oxidative, Anti-Inflammatory and Anti-Apoptotic Effects of Flavonols: Targeting Nrf2, NF-κB and p53 Pathways in Neurodegeneration

Anti-Oxidative, Anti-Inflammatory and Anti-Apoptotic Effects of Flavonols: Targeting Nrf2, NF-κB and p53 Pathways in Neurodegeneration

The Relevance of Amyloid β-Calmodulin Complexation in Neurons and Brain Degeneration in Alzheimer’s Disease

Targeted Lipidomics of Mitochondria in a Cellular Alzheimer’s Disease Model

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