Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: recent advances

Wang, Wenzhang; Zhao, Fanpeng; Ma, Xiaopin; Perry, George; Zhu, Xiongwei

doi:10.1186/s13024-020-00376-6

Cited by 610 publications

(403 citation statements)

References 257 publications

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“…Mammalian cells express multiple ROS-scavenging mechanisms that equip them with an antioxidant capacity [ 4 ]. However, a variety of pathological factors, both endogenous and exogenous, for example, reperfusion following transient ischemia, accumulation and aggregation of amyloid-β (Aβ) peptides, misfolded α-synuclein proteins, mitochondrial dysfunction, metabolism, infection, drug overdose, nanoparticles (NPs) and particulate matters (PMs) in polluted ambient air, are known to stimulate excessive generation of ROS, impair the antioxidant capacity of cells, or both [ [5] , [6] , [7] , [8] , [9] , [10] , [11] , [12] , [13] , [14] ]. Such an imbalance can lead to the accumulation of ROS at high levels that induces a noxious condition termed oxidative stress (OS) [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

TRPM2 channel-mediated cell death: An important mechanism linking oxidative stress-inducing pathological factors to associated pathological conditions

Malko

Jiang

2020

Redox Biology

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Oxidative stress resulting from the accumulation of high levels of reactive oxygen species is a salient feature of, and a well-recognised pathological factor for, diverse pathologies. One common mechanism for oxidative stress damage is via the disruption of intracellular ion homeostasis to induce cell death. TRPM2 is a non-selective Ca 2+ -permeable cation channel with a wide distribution throughout the body and is highly sensitive to activation by oxidative stress. Recent studies have collected abundant evidence to show its important role in mediating cell death induced by miscellaneous oxidative stress-inducing pathological factors, both endogenous and exogenous, including ischemia/reperfusion and the neurotoxicants amyloid-β peptides and MPTP/MPP + that cause neuronal demise in the brain, myocardial ischemia/reperfusion, proinflammatory mediators that disrupt endothelial function, diabetogenic agent streptozotocin and diabetes risk factor free fatty acids that induce loss of pancreatic β-cells, bile acids that damage pancreatic acinar cells, renal ischemia/reperfusion and albuminuria that are detrimental to kidney cells, acetaminophen that triggers hepatocyte death, and nanoparticles that injure pericytes. Studies have also shed light on the signalling mechanisms by which these pathological factors activate the TRPM2 channel to alter intracellular ion homeostasis leading to aberrant initiation of various cell death pathways. TRPM2-mediated cell death thus emerges as an important mechanism in the pathogenesis of conditions including ischemic stroke, neurodegenerative diseases, cardiovascular diseases, diabetes, pancreatitis, chronic kidney disease, liver damage and neurovascular injury. These findings raise the exciting perspective of targeting the TRPM2 channel as a novel therapeutic strategy to treat such oxidative stress-associated diseases.

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Section: Introductionmentioning

confidence: 99%

TRPM2 channel-mediated cell death: An important mechanism linking oxidative stress-inducing pathological factors to associated pathological conditions

Malko

Jiang

2020

Redox Biology

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“…Moreover, mitochondrial dysfunctions also play a key role in various modalities of cellular death, including apoptosis, necroptosis, pyroptosis and ferroptosis [68]. Therefore, dysfunctional mitochondria are able to promote the initiation and progression of multiple CNS disorders, including ischemic stroke [70], SCI [71], and neurodegenerative diseases [72], the latter of which include Parkinson's disease [72][73][74], Alzheimer's disease (AD) [72,74,75], amyotrophic lateral sclerosis (ALS) [72,74] and multiple sclerosis (MS) [72,74].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Transplantation Improves Stroke-Induced Brain Injury: Possible Involvement of Selective Component Recombination

Xie¹,

Zeng²,

Xu³

et al. 2020

Preprint

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Background: Ischemic stroke results in high morbidity and mortality, and mitochondrial dysfunctions play a crucial role in the associated pathological process. Although exogenous mitochondria were used to treat ischemic stroke-induced brain injury, its effects and related mechanisms remain poorly understood, as is the fate of exogenous mitochondria during/after internalization by targeted cells. Methods: The mitochondrial morphology, membrane potential, DNA copy number, mitochondrial stress, metabolic characteristics and tumorigenicity of mNSCs and Neuro-2a cells were evaluated. Hypoxia/reoxygenation-induced cell injury was performed, and after mitochondrial supplementation, the viability, ROS levels, apoptosis and transcriptomic changes were assessed by CCK-8, DCHF-DA probes, flow cytometry, WB and next-generation sequencing analyses. The fate of exogenous mitochondria was further explored using fluorescent dyes and fusion protein analyses during/after internalization by targeted cells. Rat tMCAO models were generated using a suture-occluded method, and at 24 h after mitochondrial transplantation, behavioral changes and brain infarction areas were estimated by multiple score scales and TTC staining, respectively. Results: In this research, we found that mitochondria of Neuro-2a cells had some notable differences compared to that of mNSCs on mitochondrial membrane potential, DNA copy number, stress response and metabolic characteristics, but their shapes were similar and were both no tumorigenicity. Exogenous mitochondrial treatment could increase the cellular viability in an oxygen-dependent pattern, decrease the cellular ROS generation and apoptosis, and alter the transcriptomic characteristics after subjected to hypoxia/reoxygenation in vitro. Selective component recombination might occur during/after internalization of exogenous mitochondria by host cells and was observed with mitochondrial fluorescent dyes and engineered fusion protein. Moreover, mitochondrial transplantation could significantly improve tMCAO-induced rat neurobehavioral deficiency and brain infarction. Conclusions: The results of our present study offer a promising therapeutic strategy for ischemia/reperfusion-induced brain injury and provide preliminary insights regarding the effects and fate of exogenous mitochondria during/after being internalized into host cells.

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“…One of the main contributors in the pathogenesis of AD is mitochondrial dysfunction, as the healthy and functional mitochondria not only supports neuronal activity by providing sufficient energy for mitochondrial functions of neurons but also protects neurons by minimizing mitochondrial oxidative damage [97]. Mitochondria are the major energy source providing ATP through oxidative phosphorylation to maintain the neuronal physiology and homeostasis [98].…”

Section: Pathophysiology Of Alzheimer's Disease (Ad)mentioning

confidence: 99%

Antioxidant and Neuroprotective Effects of Caffeine against Alzheimer’s and Parkinson’s Disease: Insight into the Role of Nrf-2 and A2AR Signaling

et al. 2020

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This paper reviews the results of studies conducted on the role of caffeine in the management of different neurological disorders, such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). To highlight the potential role of caffeine in managing different neurodegenerative diseases, we identified studies by searching PubMed, Web of Science, and Google Scholar by scrutinizing the lists of pertinent publications. According to the collected overall findings, caffeine may reduce the elevated oxidative stress; inhibit the activation of adenosine A2A, thereby regulating the accumulation of Aβ; reduce the hyperphosphorylation of tau; and reduce the accumulation of misfolded proteins, such as α-synuclein, in Alzheimer’s and Parkinson’s diseases. The studies have suggested that caffeine has promising protective effects against different neurodegenerative diseases and that these effects may be used to tackle the neurological diseases and/or their consequences. Here, we review the ongoing research on the role of caffeine in the management of different neurodegenerative disorders, focusing on AD and PD. The current findings suggest that caffeine produces potent antioxidant, inflammatory, and anti-apoptotic effects against different models of neurodegenerative disease, including AD, PD, and other neurodegenerative disorders. Caffeine has shown strong antagonistic effects against the adenosine A2A receptor, which is a microglial receptor, and strong agonistic effects against nuclear-related factor-2 (Nrf-2), thereby regulating the cellular homeostasis at the brain by reducing oxidative stress, neuroinflammation, regulating the accumulation of α-synuclein in PD and tau hyperphosphorylation, amyloidogenesis, and synaptic deficits in AD, which are the cardinal features of these neurodegenerative diseases.

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Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: recent advances

Cited by 610 publications

References 257 publications

TRPM2 channel-mediated cell death: An important mechanism linking oxidative stress-inducing pathological factors to associated pathological conditions

TRPM2 channel-mediated cell death: An important mechanism linking oxidative stress-inducing pathological factors to associated pathological conditions

Mitochondrial Transplantation Improves Stroke-Induced Brain Injury: Possible Involvement of Selective Component Recombination

Antioxidant and Neuroprotective Effects of Caffeine against Alzheimer’s and Parkinson’s Disease: Insight into the Role of Nrf-2 and A2AR Signaling

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