scholarly journals Amyloid Beta and Phosphorylated Tau-Induced Defective Autophagy and Mitophagy in Alzheimer’s Disease

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 488 ◽  
Author(s):  
P. Hemachandra Reddy ◽  
Darryll MA Oliver
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Amyloid Beta ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Memory Loss ◽  
Disease Process ◽  
Neuronal Loss ◽  
Cellular Debris

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by memory loss and multiple cognitive impairments. Several decades of intense research have revealed that multiple cellular changes are implicated in the development and progression of AD, including mitochondrial damage, synaptic dysfunction, amyloid beta (Aβ) formation and accumulation, hyperphosphorylated tau (P-Tau) formation and accumulation, deregulated microRNAs, synaptic damage, and neuronal loss in patients with AD. Among these, mitochondrial dysfunction and synaptic damage are early events in the disease process. Recent research also revealed that Aβ and P-Tau-induced defective autophagy and mitophagy are prominent events in AD pathogenesis. Age-dependent increased levels of Aβ and P-Tau reduced levels of several autophagy and mitophagy proteins. In addition, abnormal interactions between (1) Aβ and mitochondrial fission protein Drp1; (2) P-Tau and Drp1; and (3) Aβ and PINK1/parkin lead to an inability to clear damaged mitochondria and other cellular debris from neurons. These events occur selectively in affected AD neurons. The purpose of our article is to highlight recent developments of a Aβ and P-Tau-induced defective autophagy and mitophagy in AD. This article also summarizes several aspects of mitochondrial dysfunction, including abnormal mitochondrial dynamics (increased fission and reduced fusion), defective mitochondrial biogenesis, reduced ATP, increased free radicals and lipid peroxidation, and decreased cytochrome c oxidase (COX) activity and calcium dyshomeostasis in AD pathogenesis. Our article also discusses how reduced levels of Drp1, Aβ, and P-Tau can enhance the clearance of damaged mitochondria and other cellular debris by autophagy and mitophagy mechanisms.

scholarly journals ROLE OF MITOCHONDRIAL DISFUNCTION IN THE DEVELOPMENT OF ALZHEIMER’S DISEASE

2021 ◽  
Vol 67 (1) ◽  
pp. 57-66
Author(s):  
V.V. Ganzha ◽  
◽  
E.A. Lukyanetz ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Tau Protein ◽  
Mitochondrial Dynamics ◽  
Memory Loss ◽  
Disease Process ◽  
Hyperphosphorylated Tau Protein ◽  
Amyloid Aβ

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by memory loss and multiple cognitive impairments. Several decades of intensive research have shown that multicellular changes are involved in AD’s development and progression, including mitochondrial damage, synaptic dysfunction, formation and accumulation of beta-amyloid (Aβ), formation and accumulation of hyperphosphorylated tau protein, and loss of neurons in patients with this disease. Among them, mitochondrial dysfunction and synaptic damage are the primary manifestations in the disease process. Recent studies have also shown that defective mitophagy caused by Aβ and tau protein are the main indicators in AD’s pathogenesis. This review includes an overview of recent researches on the role of mitochondria in AD development. The review summarizes several aspects of mitochondrial dysfunction, including abnormal mitochondrial dynamics, changes in mitochondrial DNA, and calcium dyshomeostasis in AD pathogenesis

scholarly journals The Role of Oxidative Stress-Induced Epigenetic Alterations in Amyloid-βProduction in Alzheimer’s Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Li Zuo ◽  
Benjamin T. Hemmelgarn ◽  
Chia-Chen Chuang ◽  
Thomas M. Best
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Treatment Options ◽  
Memory Loss ◽  
The United States ◽  
Traditional Medicines ◽  
Progressive Neurodegeneration ◽  
Antioxidant Supplements

An increasing number of studies have proposed a strong correlation between reactive oxygen species (ROS)-induced oxidative stress (OS) and the pathogenesis of Alzheimer’s disease (AD). With over five million people diagnosed in the United States alone, AD is the most common type of dementia worldwide. AD includes progressive neurodegeneration, followed by memory loss and reduced cognitive ability. Characterized by the formation of amyloid-beta (Aβ) plaques as a hallmark, the connection between ROS and AD is compelling. Analyzing the ROS response of essential proteins in the amyloidogenic pathway, such as amyloid-beta precursor protein (APP) and beta-secretase (BACE1), along with influential signaling programs of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and c-Jun N-terminal kinase (JNK), has helped visualize the path between OS and Aβoverproduction. In this review, attention will be paid to significant advances in the area of OS, epigenetics, and their influence on Aβplaque assembly. Additionally, we aim to discuss available treatment options for AD that include antioxidant supplements, Asian traditional medicines, metal-protein-attenuating compounds, and histone modifying inhibitors.

scholarly journals Amyloid Beta Mediated Mitochondrial Dysfunction in Alzheimer's disease: A Mini Review.

2019 ◽  
Vol 9 (3) ◽  
pp. 2981-2990
Author(s):  
Vivek Sharma . ◽  
Priyanka Nagu . ◽  
Raneev Thakur . ◽  
Pankaj Sharma . ◽  
Harish Kumar .
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Amyloid Beta

scholarly journals Epoxyeicosatrienoic acids pretreatment improves amyloid β-induced mitochondrial dysfunction in cultured rat hippocampal astrocytes

2014 ◽  
Vol 306 (4) ◽  
pp. H475-H484 ◽  
Author(s):  
Pallabi Sarkar ◽  
Ivan Zaja ◽  
Martin Bienengraeber ◽  
Kevin R. Rarick ◽  
Maia Terashvili ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Rat Brain ◽  
Clinical Symptoms ◽  
Mitochondrial Dynamics ◽  
Amyloid Β ◽  
Cellular Respiration ◽  
Epoxyeicosatrienoic Acids ◽  
Hippocampal Astrocytes

Amyloid-β (Aβ) has long been implicated as a causative protein in Alzheimer's disease. Cellular Aβ accumulation is toxic and causes mitochondrial dysfunction, which precedes clinical symptoms of Alzheimer's disease pathology. In the present study, we explored the possible use of epoxyeicosatrienoic acids (EETs), epoxide metabolites of arachidonic acid, as therapeutic target against Aβ-induced mitochondrial impairment using cultured neonatal hippocampal astrocytes. Inhibition of endogenous EET production by a selective epoxygenase inhibitor, MS-PPOH, caused a greater reduction in mitochondrial membrane potential in the presence of Aβ (1, 10 μM) exposure versus absence of Aβ. MS-PPOH preincubation also aggravated Aβ-induced mitochondrial fragmentation. Preincubation of the cells with either 14,15- or 11,12-EET prevented this mitochondrial depolarization and fragmentation. EET pretreatment also further improved the reduction observed in mitochondrial oxygen consumption in the presence of Aβ. Preincubation of the cells with EETs significantly improved cellular respiration under basal condition and in the presence of the protonophore, carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP). The uncoupling of ATP synthase from the electron transfer chain that occurred in Aβ-treated cells was also prevented by preincubation with EETs. Lastly, cellular reactive oxygen species production, a hallmark of Aβ toxicity, also showed significant reduction in the presence of EETs. We have previously shown that Aβ reduces EET synthesis in rat brain homogenates and cultured hippocampal astrocytes and neurons (Sarkar P, Narayanan J, Harder DR. Differential effect of amyloid beta on the cytochrome P450 epoxygenase activity in rat brain. Neuroscience 194: 241–249, 2011). We conclude that reduction of endogenous EETs may be one of the mechanisms through which Aβ inflicts toxicity and thus supplementing the cells with exogenous EETs improves mitochondrial dynamics and prevents metabolic impairment.

scholarly journals IL-33 ameliorates Alzheimer’s disease-like pathology and cognitive decline

2016 ◽  
Vol 113 (19) ◽  
pp. E2705-E2713 ◽  
Author(s):  
Amy K. Y. Fu ◽  
Kwok-Wang Hung ◽  
Michael Y. F. Yuen ◽  
Xiaopu Zhou ◽  
Deejay S. Y. Mak ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune Response ◽  
Innate Immune Response ◽  
Memory Loss ◽  
Neuronal Loss ◽  
Innate Immune ◽  
Therapeutic Role ◽  
Potential Therapeutic Role ◽  
The Brain

Alzheimer’s disease (AD) is a devastating condition with no known effective treatment. AD is characterized by memory loss as well as impaired locomotor ability, reasoning, and judgment. Emerging evidence suggests that the innate immune response plays a major role in the pathogenesis of AD. In AD, the accumulation of β-amyloid (Aβ) in the brain perturbs physiological functions of the brain, including synaptic and neuronal dysfunction, microglial activation, and neuronal loss. Serum levels of soluble ST2 (sST2), a decoy receptor for interleukin (IL)-33, increase in patients with mild cognitive impairment, suggesting that impaired IL-33/ST2 signaling may contribute to the pathogenesis of AD. Therefore, we investigated the potential therapeutic role of IL-33 in AD, using transgenic mouse models. Here we report that IL-33 administration reverses synaptic plasticity impairment and memory deficits in APP/PS1 mice. IL-33 administration reduces soluble Aβ levels and amyloid plaque deposition by promoting the recruitment and Aβ phagocytic activity of microglia; this is mediated by ST2/p38 signaling activation. Furthermore, IL-33 injection modulates the innate immune response by polarizing microglia/macrophages toward an antiinflammatory phenotype and reducing the expression of proinflammatory genes, including IL-1β, IL-6, and NLRP3, in the cortices of APP/PS1 mice. Collectively, our results demonstrate a potential therapeutic role for IL-33 in AD.

Lipoprotein-Based Nanoparticles Rescue the Memory Loss of Mice with Alzheimer’s Disease by Accelerating the Clearance of Amyloid-Beta

ACS Nano ◽  
2014 ◽  
Vol 8 (3) ◽  
pp. 2345-2359 ◽  
Author(s):  
Qingxiang Song ◽  
Meng Huang ◽  
Lei Yao ◽  
Xiaolin Wang ◽  
Xiao Gu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Memory Loss

scholarly journals Mitochondrial Deficits With Neural and Social Damage in Early-Stage Alzheimer’s Disease Model Mice

2021 ◽  
Vol 13 ◽  
Author(s):  
Afzal Misrani ◽  
Sidra Tabassum ◽  
Qingwei Huo ◽  
Sumaiya Tabassum ◽  
Jinxiang Jiang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Neuronal Morphology ◽  
Therapeutic Interventions ◽  
Early Event ◽  
Mitochondrial Morphology

Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide. Mitochondrial dysfunction is thought to be an early event in the onset and progression of AD; however, the precise underlying mechanisms remain unclear. In this study, we investigated mitochondrial proteins involved in organelle dynamics, morphology and energy production in the medial prefrontal cortex (mPFC) and hippocampus (HIPP) of young (1∼2 months), adult (4∼5 months) and aged (9∼10, 12∼18 months) APP/PS1 mice. We observed increased levels of mitochondrial fission protein, Drp1, and decreased levels of ATP synthase subunit, ATP5A, leading to abnormal mitochondrial morphology, increased oxidative stress, glial activation, apoptosis, and altered neuronal morphology as early as 4∼5 months of age in APP/PS1 mice. Electrophysiological recordings revealed abnormal miniature excitatory postsynaptic current in the mPFC together with a minor connectivity change between the mPFC and HIPP, correlating with social deficits. These results suggest that abnormal mitochondrial dynamics, which worsen with disease progression, could be a biomarker of early-stage AD. Therapeutic interventions that improve mitochondrial function thus represent a promising approach for slowing the progression or delaying the onset of AD.

scholarly journals Mitochondrial Dysfunction and Oxidative Stress in Alzheimer’s Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Afzal Misrani ◽  
Sidra Tabassum ◽  
Li Yang
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Morphology ◽  
Therapeutic Approaches ◽  
The Impact ◽  
And Oxidative Stress

Mitochondria play a pivotal role in bioenergetics and respiratory functions, which are essential for the numerous biochemical processes underpinning cell viability. Mitochondrial morphology changes rapidly in response to external insults and changes in metabolic status via fission and fusion processes (so-called mitochondrial dynamics) that maintain mitochondrial quality and homeostasis. Damaged mitochondria are removed by a process known as mitophagy, which involves their degradation by a specific autophagosomal pathway. Over the last few years, remarkable efforts have been made to investigate the impact on the pathogenesis of Alzheimer’s disease (AD) of various forms of mitochondrial dysfunction, such as excessive reactive oxygen species (ROS) production, mitochondrial Ca2+ dyshomeostasis, loss of ATP, and defects in mitochondrial dynamics and transport, and mitophagy. Recent research suggests that restoration of mitochondrial function by physical exercise, an antioxidant diet, or therapeutic approaches can delay the onset and slow the progression of AD. In this review, we focus on recent progress that highlights the crucial role of alterations in mitochondrial function and oxidative stress in the pathogenesis of AD, emphasizing a framework of existing and potential therapeutic approaches.

Alterations in Mitochondrial Dynamic-related Genes in the Peripheral Blood of Alzheimer’s Disease Patients

2020 ◽  
Vol 17 (7) ◽  
pp. 616-625
Author(s):  
Nattaporn Pakpian ◽  
Kamonrat Phopin ◽  
Kuntida Kitidee ◽  
Piyarat Govitrapong ◽  
Prapimpun Wongchitrat
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Performance ◽  
Peripheral Blood ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Pathological Feature ◽  
Mrna Levels ◽  
Healthy Controls ◽  
Expression Levels

Background: Mitochondrial dysfunction is a pathological feature that manifests early in the brains of patients with Alzheimer’s Disease (AD). The disruption of mitochondrial dynamics contributes to mitochondrial morphological and functional impairments. Our previous study demonstrated that the expression of genes involved in amyloid beta generation was altered in the peripheral blood of AD patients. Objective: The aim of this study was to further investigate the relative levels of mitochondrial genes involved in mitochondrial dynamics, including mitochondrial fission and fusion, and mitophagy in peripheral blood samples from patients with AD compared to healthy controls. Methods: The mRNA levels were analyzed by real-time polymerase chain reaction. Gene expression profiles were assessed in relation to cognitive performance. Results: Significant changes were observed in the mRNA expression levels of fission-related genes; Fission1 (FIS1) levels in AD subjects were significantly higher than those in healthy controls, whereas Dynamin- related protein 1 (DRP1) expression was significantly lower in AD subjects. The levels of the mitophagy-related genes, PTEN-induced kinase 1 (PINK1) and microtubule-associated protein 1 light chain 3 (LC3), were significantly increased in AD subjects and elderly controls compared to healthy young controls. The mRNA levels of Parkin (PARK2) were significantly decreased in AD. Correlations were found between the expression levels of FIS1, DRP1 and PARK2 and cognitive performance scores. Conclusion: Alterations in mitochondrial dynamics in the blood may reflect impairments in mitochondrial functions in the central and peripheral tissues of AD patients. Mitochondrial fission, together with mitophagy gene profiles, might be potential considerations for the future development of blood-based biomarkers for AD.

Sign in / Sign up

Export Citation Format

Share Document