scholarly journals Mitochondrial Dysfunction: Different Routes to Alzheimer’s Disease Therapy

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Pasquale Picone ◽  
Domenico Nuzzo ◽  
Luca Caruana ◽  
Valeria Scafidi ◽  
Marta Di Carlo
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Permeability Transition ◽  
Mitochondrial Protein ◽  
Radical Scavenging ◽  
Permeability Transition ◽  
Oxidation Potential ◽  
Mitochondrial Functions

Mitochondria are dynamic ATP-generating organelle which contribute to many cellular functions including bioenergetics processes, intracellular calcium regulation, alteration of reduction-oxidation potential of cells, free radical scavenging, and activation of caspase mediated cell death. Mitochondrial functions can be negatively affected by amyloidβpeptide (Aβ), an important component in Alzheimer’s disease (AD) pathogenesis, and Aβcan interact with mitochondria and cause mitochondrial dysfunction. One of the most accepted hypotheses for AD onset implicates that mitochondrial dysfunction and oxidative stress are one of the primary events in the insurgence of the pathology. Here, we examine structural and functional mitochondrial changes in presence of Aβ. In particular we review data concerning Aβimport into mitochondrion and its involvement in mitochondrial oxidative stress, bioenergetics, biogenesis, trafficking, mitochondrial permeability transition pore (mPTP) formation, and mitochondrial protein interaction. Moreover, the development of AD therapy targeting mitochondria is also discussed.

A Protective Role of Translocator Protein in Alzheimer’s Disease Brain

2020 ◽  
Vol 17 (1) ◽  
pp. 3-15 ◽  
Author(s):  
Marianna E. Jung
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Permeability Transition ◽  
Neuronal Degeneration ◽  
Mitochondrial Protein ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Protective Role ◽  
Translocator Protein ◽  
Initial Increase

Translocator Protein (18 kDa) (TSPO) is a mitochondrial protein that locates cytosol cholesterol to mitochondrial membranes to begin the synthesis of steroids including neurotrophic neurosteroids. TSPO is abundantly present in glial cells that support neurons and respond to neuroinflammation. Located at the outer membrane of mitochondria, TSPO regulates the opening of mitochondrial permeability transition pore (mPTP) that controls the entry of molecules necessary for mitochondrial function. TSPO is linked to neurodegenerative Alzheimer’s Disease (AD) such that TSPO is upregulated in the brain of AD patients and signals AD-induced adverse changes in brain. The initial increase in TSPO in response to brain insults remains elevated to repair cellular damages and perhaps to prevent further neuronal degeneration as AD progresses. To exert such protective activities, TSPO increases the synthesis of neuroprotective steroids, decreases neuroinflammation, limits the opening of mPTP, and reduces the generation of reactive oxygen species. The beneficial effects of TSPO on AD brain are manifested as the attenuation of neurotoxic amyloid β and mitochondrial dysfunction accompanied by the improvement of memory and cognition. However, the protective activities of TSPO appear to be temporary and eventually diminish as the severity of AD becomes profound. Timely treatment with TSPO agonists/ligands before the loss of endogenous TSPO’s activity may promote the protective functions and may extend neuronal survival.

scholarly journals Mitochondrial Permeability Transition: A Pore Intertwines Brain Aging and Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 649
Author(s):  
Kun Jia ◽  
Heng Du
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Brain Aging ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Brain Disorders ◽  
Mitochondrial Permeability

Advanced age is the greatest risk factor for aging-related brain disorders including Alzheimer’s disease (AD). However, the detailed mechanisms that mechanistically link aging and AD remain elusive. In recent years, a mitochondrial hypothesis of brain aging and AD has been accentuated. Mitochondrial permeability transition pore (mPTP) is a mitochondrial response to intramitochondrial and intracellular stresses. mPTP overactivation has been implicated in mitochondrial dysfunction in aging and AD brains. This review summarizes the up-to-date progress in the study of mPTP in aging and AD and attempts to establish a link between brain aging and AD from a perspective of mPTP-mediated mitochondrial dysfunction.

scholarly journals Correction of Mitochondrial Dysfunction by 4-Hydroxy-3,5-Ditretbutyl Cinnamic Acid in Experimental Alzheimer’s Disease Induced by Aβ Injection in Rats

2020 ◽  
Vol 27 (3) ◽  
pp. 313-325
Author(s):  
Dmitry Igorevich Pozdnyakov ◽  
Andrey Voronkov
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Cinnamic Acid ◽  
Mitochondrial Function ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Morris Water Maze Test ◽  
Cellular Respiration ◽  
Β Amyloid

Background: Alzheimer’s disease is the main form of dementia, which affects more than46 million people every year. In the pathogenesis of Alzheimer’s disease, a significant roleplayed mitochondrial dysfunction, which is a promising pharmacotherapeutic target ofneuroprotective therapy. In this regard, this study aimed to evaluate the effect of the 4-hydroxy-3,5-ditretbutyl cinnamic acid on changes of mitochondrial function in experimental Alzheimer’sdisease induced by Aβ injection in rats. Methods: Alzheimer’s disease was modeled on Wistar rats by injecting a fragment of β-amyloid(Aß 1-42) into the CA1 part of the hippocampus. The test-compound (4-hydroxy-3,5-ditretbutylcinnamic acid, 100 mg/kg, per os) and the reference drugs (resveratrol, 20 mg/kg, per os andEGB671, 100 mg/kg, per os) were administered for 60 days after surgery. The restoration of amemorable trace in animals was evaluated in the Morris water maze test. The concentrationof β -amyloid, Tau-protein, and changes in parameters characterizing mitochondrial function(cellular respiration, concentration of mitochondrial ROS, activity of apoptosis reactions(caspase-3 and apoptosis induced factor) were also determined. Results: This study showed that the administration of 4-hydroxy-3,5-ditretbutyl cinnamic acidat a dose of 100 mg/kg (per os) in rats with reproduced Alzheimer’s disease contributed to thenormalization of mitochondrial respiratory function. It was expressed in the normalizationof aerobic metabolism, increased activity of respiratory complexes and stabilization ofmitochondrial membrane potential. Also, when animals were treated with 4-hydroxy-3,5-ditretbutyl cinnamic acid, there was a decrease in the concentration of intracellular calcium(by 39.7% (p<0.05)), the intensity of apoptosis reactions, and an increase of the latent time ofthe mitochondrial permeability transition pore opening (by 3.8 times (p<0.05)), and decreasesH2O2 concentration (by 21.2% (p<0.05)). Conclusion: In the course of this study, it was found that 4-hydroxy-3,5-ditretbutyl cinnamicacid exceeds the value of neuroprotective action in compared to the reference agents –resveratrol (20 mg/kg) and Ginkgo biloba extract (EGB671, 100 mg/kg).

scholarly journals Mitochondria, Amyloid β, and Alzheimer's Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-5 ◽  
Author(s):  
Ryan D. Readnower ◽  
Andrew D. Sauerbeck ◽  
Patrick G. Sullivan
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Permeability Transition ◽  
Amyloid Β ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Enzymes ◽  
Cyclophilin D ◽  
Ample Evidence

Hypometabolism is a hallmark of Alzheimer's disease (AD) and implicates a mitochondrial role in the neuropathology associated with AD. Mitochondrial amyloid-beta (Aβ) accumulation precedes extracellular Aβdeposition. In addition to increasing oxidative stress, Aβhas been shown to directly inhibit mitochondrial enzymes. Inhibition of mitochondrial enzymes as a result of oxidative damage or Aβinteraction perpetuates oxidative stress and leads to a hypometabolic state. Additionally, Aβhas also been shown to interact with cyclophilin D, a component of the mitochondrial permeability transition pore, which may promote cell death. Therefore, ample evidence exists indicating that the mitochondrion plays a vital role in the pathophysiology observed in AD.

scholarly journals Metabolism: A Novel Shared Link between Diabetes Mellitus and Alzheimer’s Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Yanan Sun ◽  
Cao Ma ◽  
Hui Sun ◽  
Huan Wang ◽  
Wei Peng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Metabolic Disease ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Diabetic Patients ◽  
Increased Risk ◽  
Impaired Insulin ◽  
The Brain

As a chronic metabolic disease, diabetes mellitus (DM) is broadly characterized by elevated levels of blood glucose. Novel epidemiological studies demonstrate that some diabetic patients have an increased risk of developing dementia compared with healthy individuals. Alzheimer’s disease (AD) is the most frequent cause of dementia and leads to major progressive deficits in memory and cognitive function. Multiple studies have identified an increased risk for AD in some diabetic populations, but it is still unclear which diabetic patients will develop dementia and which biological characteristics can predict cognitive decline. Although few mechanistic metabolic studies have shown clear pathophysiological links between DM and AD, there are several plausible ways this may occur. Since AD has many characteristics in common with impaired insulin signaling pathways, AD can be regarded as a metabolic disease. We conclude from the published literature that the body’s diabetic status under certain circumstances such as metabolic abnormalities can increase the incidence of AD by affecting glucose transport to the brain and reducing glucose metabolism. Furthermore, due to its plentiful lipid content and high energy requirement, the brain’s metabolism places great demands on mitochondria. Thus, the brain may be more susceptible to oxidative damage than the rest of the body. Emerging evidence suggests that both oxidative stress and mitochondrial dysfunction are related to amyloid-β (Aβ) pathology. Protein changes in the unfolded protein response or endoplasmic reticulum stress can regulate Aβ production and are closely associated with tau protein pathology. Altogether, metabolic disorders including glucose/lipid metabolism, oxidative stress, mitochondrial dysfunction, and protein changes caused by DM are associated with an impaired insulin signal pathway. These metabolic factors could increase the prevalence of AD in diabetic patients via the promotion of Aβ pathology.

scholarly journals Aldehyde dehydrogenase 2 activity and aldehydic load contribute to neuroinflammation and Alzheimer’s disease related pathology

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Amit U. Joshi ◽  
Lauren D. Van Wassenhove ◽  
Kelsey R. Logas ◽  
Paras S. Minhas ◽  
Katrin I. Andreasson ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Alcohol Consumption ◽  
Mitochondrial Dysfunction ◽  
Aldehyde Dehydrogenase ◽  
Cortical Neurons ◽  
Aldehyde Dehydrogenase 2 ◽  
East Asians

AbstractAldehyde dehydrogenase 2 deficiency (ALDH2*2) causes facial flushing in response to alcohol consumption in approximately 560 million East Asians. Recent meta-analysis demonstrated the potential link between ALDH2*2 mutation and Alzheimer’s Disease (AD). Other studies have linked chronic alcohol consumption as a risk factor for AD. In the present study, we show that fibroblasts of an AD patient that also has an ALDH2*2 mutation or overexpression of ALDH2*2 in fibroblasts derived from AD patients harboring ApoE ε4 allele exhibited increased aldehydic load, oxidative stress, and increased mitochondrial dysfunction relative to healthy subjects and exposure to ethanol exacerbated these dysfunctions. In an in vivo model, daily exposure of WT mice to ethanol for 11 weeks resulted in mitochondrial dysfunction, oxidative stress and increased aldehyde levels in their brains and these pathologies were greater in ALDH2*2/*2 (homozygous) mice. Following chronic ethanol exposure, the levels of the AD-associated protein, amyloid-β, and neuroinflammation were higher in the brains of the ALDH2*2/*2 mice relative to WT. Cultured primary cortical neurons of ALDH2*2/*2 mice showed increased sensitivity to ethanol and there was a greater activation of their primary astrocytes relative to the responses of neurons or astrocytes from the WT mice. Importantly, an activator of ALDH2 and ALDH2*2, Alda-1, blunted the ethanol-induced increases in Aβ, and the neuroinflammation in vitro and in vivo. These data indicate that impairment in the metabolism of aldehydes, and specifically ethanol-derived acetaldehyde, is a contributor to AD associated pathology and highlights the likely risk of alcohol consumption in the general population and especially in East Asians that carry ALDH2*2 mutation.

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