AUCTORES
Globalize your Research
Short Communication | DOI: https://doi.org/10.31579/2578-8868/026
*Corresponding Author: Ruth Angale , Department of NeuroBiology , Iran
Citation: Ruth Angale , Nickell Taveley, The Role of Mitochondria in Alzheimer's disease: Neurodegenerative Disease and Future Therapeutic Options DOI : 10.31579/2578-8868/026
Copyright: © 2018 Ruth Angale This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Received: 02 January 2018 | Accepted: 20 January 2018 | Published: 05 February 2018
Keywords: alzheimer′s disease; mitochondria; bioenergetics; mitochondrial dna; neuroinflammation; mitohormesis; caloric restriction; hypometabolism; mitophagy;
Mitochondria are cytoplasmic organelles responsible for life and death. Extensive evidence from animal and clinical studies suggests that mitochondria play a critical role in aging, cancer, diabetes and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. Several lines of research suggest that mitochondrial oxidative damage is an important cellular change in most late-onset neurodegenerative diseases. Further, emerging evidence suggests that structural changes in mitochondria, including increased mitochondrial fragmentation and decreased mitochondrial fusion, are critical factors associated with mitochondrial dysfunction and cell death in aging and age-related diseases. In addition, epigenetic factors and lifestyle activities may contribute to selective disease susceptibility for each of these diseases. This paper discusses research that has elucidated features of mitochondria that are associated with cellular dysfunction in aging and neurodegenerative diseases. This paper also discusses mitochondrial abnormalities and potential mitochondrial therapeutics in AD.
Alzheimer's disease (AD) is characterized by neuronal loss and gradual cognitive impairment. AD is the leading cause of dementia worldwide and the incidence is increasing rapidly, with diagnoses expected to triple by the year 2050. Impaired cholinergic transmission is a major role player in the rapid deterioration associated with AD, primarily as a result of increased acetylcholinesterase (AChE) in the AD brain, responsible for reducing the amount of acetylcholine (ACh). Current drug therapies, known as AChE inhibitors (AChEIs), target this heightened level of AChE in an attempt to slow disease progression. AChEIs have only showed success in the treatment of mild to moderate AD symptoms, with the glutamate inhibitor memantine being the most common drug prescribed for the management of severe AD.
AD is categorized into two major forms: sporadic AD (sAD) and familial AD (fAD) with < 10>
Additional risk genes that have been identified by genome-wide association studies (GWAS) include: the gene for clusterin (CLU) also known as apolipoprotein J (localized on chromosome 8), the gene encoding the complement component (3b/4b) receptor 1 (CR1) (chromosome 1), the gene encoding PI-binding clathrin assembly protein (PICALM) (chromosome 11), the gene encoding the bridging integrator 1 (BIN1) (chromosome 2), and the disabled homolog 1 (DAB1) (chromosome 1). Additional novel risk loci associated with sAD are: sortilin-like receptor 1 (SORL1), triggering receptor expressed on myeloid cells 2 (TREM2), the membrane-spanning 4-domains, subfamily A (MS4A), ATP-binding cassette transporter A1 and A7 (ABCA1 and 7), methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) and CD33 (Allen et al., 2012). These newly identified genes are involved in transport, lipid metabolism (Zhu et al., 2015; El gaamouch et al., 2016), immune response and APP metabolism (De Strooper and Karran, 2016).
A mitochondrion contains 2–10 copies of mtDNA (Reddy, 2008). The human mtDNA consists of a 16.5 kb, double-stranded, circular DNA molecule (Anderson et al., 1981). mtDNA contains 13 polypeptide genes that encode essential components of the ETC. mtDNA also encodes the 12S and 16S ribosomal RNA (rRNA) genes and the 22 transfer RNA (tRNA) genes required for mitochondrial protein synthesis (Reddy and Beal, 2005). Nuclear genes encode the remaining mitochondrial proteins, metabolic enzymes, DNA and RNA polymerases, ribosomal proteins, and mtDNA regulatory factors, such as mitochondrial transcription factor A. Nuclear mitochondrial proteins are synthesized in the cytoplasm and are subsequently transported into mitochondria. mtDNA is inherited exclusively from the mother and is present in thousands of copies per cell. Mitochondrial number and morphology are controlled by an equilibrium of mitochondrial fusion and fission (Chan, 2006) that is vital for metabolism, energy production, Ca2+ signaling, ROS production, apoptosis, and senescence Fusion allows the exchange of mitochondrial components including mtDNA between different mitochondria. mtDNA due to their proximity to the respiratory chain and a lack of protective histones have a very high mutation rate that is about ten times faster compared to the nuclear DNA (nDNA).
New mtDNA mutations arise frequently in the maternal lineage and initially present as a mixture of the wild-type and mutant mtDNAs, defining the so-called heteroplasmic state. mtDNA mutations are most often heteroplasmic (mixed population of normal and mutant mtDNAs). During cellular divisions, the mutant mtDNAs will be randomly segregated into the daughter's cells and the percentage of mutant mtDNAs in different cell lineages will drift toward either pure mutant or normal (or homoplasmy) (Stewart and Chinnery, 2015). As the percentage of mutant mtDNAs increases in the cell, energy output falls, resulting in an overall mitochondrial dysfunction in the cell. Hence, the ratio of mutant to normal mtDNA contributes to the severity of the disease. Severe mitochondrial damage impairs fusion resulting in fragmentation of mitochondria that are then selectively removed by an autophagic process called mitophagy.
Cell-based therapies are a promising alternative currently being developed to enable the reversal of neurodegeneration in AD either directly by replacing injured neuron or indirectly by stimulating neuronal repair via paracrine signaling at the injury site (Baraniak and McDevitt, 2010). Neurons and glial cells have successfully been generated from embryonic stem cells (ESCs), neural stem cells (NSCs), neural progenitor cells (NPCs), mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs), and induced neuronal cells (iN), induced neuronal progenitor cells (iNPCs). Transplantation of NSCs into animal models of neurodegenerative diseases, including AD, increases the total amount of mtDNA, messenger RNA and protein levels of mitochondrial biogenesis-related factors as well as protein levels of mitochondrial fission genes.
Targeting detrimental neuronal ROS at the production stage without affecting ROS signaling would be ideal in preventing and treating AD. In this regard, it has been shown that mitochondria-targeted antioxidants potently sequester reactive oxygen intermediates and confer greater protection against oxidative damage in the mitochondria than untargeted cellular antioxidants. The ability of mitochondria-targeted antioxidants to confer greater protection against oxidative damage in the mitochondria than untargeted cellular antioxidants provide has been attributed to their ability to cross the mitochondrial phospholipid bilayer and eliminate ROS where it is being generated.
Targeting the proteasome
Proteosomal activity can also be enhanced by using Pyrazolone containing small molecules which block USP14, a proteasome-associated deubiquitinating enzyme that inhibits the processing of ubiquitin–protein complexes destined for degradation by the proteasome (Lee et al., 2010). PD169316 is a novel small molecule p38 MAPK inhibitor and a very potent activator of proteasome activity enhanced Proteolysis Targeting Chimeric (PROTAC)-mediated and ubiquitin-dependent protein degradation and decreases the levels of both overexpressed and endogenous α-synuclein in a bimolecular fluorescence complementation (BiFC) assay.
Role of Aging and Epigenetic Factors in Neurodegenerative Diseases
In AD and PD, there are no differences pathologically between early onset familial patients and late onset patients. Only difference is that in late-onset patients, pathological changes occur later than in the early-onset patients. In early-onset cases, genetic mutations accelerate the disease process. In late-onset patients, in the absence of genetic mutations, age-related cellular changes control disease progression, which is why late-onset AD and PD patients take more time to exhibit pathological features. As described above, age-related mitochondrial abnormalities contribute to disease progression in late-onset AD and PD. However, if age-dependent mitochondrial abnormalities are likely factors affecting the development of AD and PD (and possibly even affecting cancer and diabetes in aged individuals), it is still unclear what makes some aged persons susceptible to PD development and others, to AD. Epigenetic factors and lifestyle activities may contribute to age-dependent susceptibility to these diseases.
Mitochondrial dysfunction is an early event in AD
Using in situ hybridization to mtDNA, immunocytochemistry of cytochrome oxidase (COX), and morphometry of electron micrographs of biopsy specimens, we demonstrated that neurons showing increased oxidative damage in AD also possessed a striking and significant increase in mtDNA and COX [. Moreover, we found that much of the mtDNA and COX was localized in the neuronal cytoplasm and, in the case of mtDNA, in vacuoles associated with lipofuscin, whereas morphometric analysis showed that mitochondria were significantly reduced in AD. Interestingly, the cellular expression of COX subunits II and IV is reduced during aging and these age-related changes are more marked in AD, suggesting that aging is a major risk factor for this disease. However, Cottrell et al. Observed that the distribution of amyloid plaques is anatomically distinct from the COX-deficient hippocampal pyramidal neurons, and the neurons containing NFT or apoptotic labeling were always COX-positive. The authors concluded that COX-deficient, succinate dehydrogenase-positive hippocampal neurons indicative of high mtDNA mutation load do not appear to be prone to apoptosis or to directly participate in the overproduction of tau or Aβ.
Mitochondrial-Directed Therapies
The discovery that mitochondrial dysfunction underlies the pathogenesis of many neurodegenerative diseases has opened a window for new therapeutic strategies aimed at preserving/ameliorating mitochondrial function. In nearly all cases where mitochondrial dysfunction contributes to disease, a major cause of damage is overproduction of ROS by mitochondria, either directly or as a secondary consequence of other malfunctions
Mitochondrial dysfunction is an early feature of AD pathology. Any damage to mitochondria by either Aβ or ROS can result in interrupting the usual mechanisms by which ROS are destroyed, therefore further increasing the number of ROS present in the organelle. It has been found that in post-mortem AD brains there is a deficit of COX, the terminal enzyme in the mitochondrial respiratory chain responsible for reducing oxygen radicals, supporting the theory that ROS are involved in the mitochondrial damage found in AD. Many antioxidants have been investigated as therapies for AD, and further studies have been carried out to find mitochondria specific antioxidants to enable a greater concentration of antioxidants to accumulate in the mitochondria, allowing a more specific method for combatting mitochondrial oxidative stress. It has been suggested that as early as 2025, prevention or effective treatment of AD may be realized.
Clearly Auctoresonline and particularly Psychology and Mental Health Care Journal is dedicated to improving health care services for individuals and populations. The editorial boards' ability to efficiently recognize and share the global importance of health literacy with a variety of stakeholders. Auctoresonline publishing platform can be used to facilitate of optimal client-based services and should be added to health care professionals' repertoire of evidence-based health care resources.
Journal of Clinical Cardiology and Cardiovascular Intervention The submission and review process was adequate. However I think that the publication total value should have been enlightened in early fases. Thank you for all.
Journal of Women Health Care and Issues By the present mail, I want to say thank to you and tour colleagues for facilitating my published article. Specially thank you for the peer review process, support from the editorial office. I appreciate positively the quality of your journal.
Journal of Clinical Research and Reports I would be very delighted to submit my testimonial regarding the reviewer board and the editorial office. The reviewer board were accurate and helpful regarding any modifications for my manuscript. And the editorial office were very helpful and supportive in contacting and monitoring with any update and offering help. It was my pleasure to contribute with your promising Journal and I am looking forward for more collaboration.
We would like to thank the Journal of Thoracic Disease and Cardiothoracic Surgery because of the services they provided us for our articles. The peer-review process was done in a very excellent time manner, and the opinions of the reviewers helped us to improve our manuscript further. The editorial office had an outstanding correspondence with us and guided us in many ways. During a hard time of the pandemic that is affecting every one of us tremendously, the editorial office helped us make everything easier for publishing scientific work. Hope for a more scientific relationship with your Journal.
The peer-review process which consisted high quality queries on the paper. I did answer six reviewers’ questions and comments before the paper was accepted. The support from the editorial office is excellent.
Journal of Neuroscience and Neurological Surgery. I had the experience of publishing a research article recently. The whole process was simple from submission to publication. The reviewers made specific and valuable recommendations and corrections that improved the quality of my publication. I strongly recommend this Journal.
Dr. Katarzyna Byczkowska My testimonial covering: "The peer review process is quick and effective. The support from the editorial office is very professional and friendly. Quality of the Clinical Cardiology and Cardiovascular Interventions is scientific and publishes ground-breaking research on cardiology that is useful for other professionals in the field.
Thank you most sincerely, with regard to the support you have given in relation to the reviewing process and the processing of my article entitled "Large Cell Neuroendocrine Carcinoma of The Prostate Gland: A Review and Update" for publication in your esteemed Journal, Journal of Cancer Research and Cellular Therapeutics". The editorial team has been very supportive.
Testimony of Journal of Clinical Otorhinolaryngology: work with your Reviews has been a educational and constructive experience. The editorial office were very helpful and supportive. It was a pleasure to contribute to your Journal.
Dr. Bernard Terkimbi Utoo, I am happy to publish my scientific work in Journal of Women Health Care and Issues (JWHCI). The manuscript submission was seamless and peer review process was top notch. I was amazed that 4 reviewers worked on the manuscript which made it a highly technical, standard and excellent quality paper. I appreciate the format and consideration for the APC as well as the speed of publication. It is my pleasure to continue with this scientific relationship with the esteem JWHCI.
This is an acknowledgment for peer reviewers, editorial board of Journal of Clinical Research and Reports. They show a lot of consideration for us as publishers for our research article “Evaluation of the different factors associated with side effects of COVID-19 vaccination on medical students, Mutah university, Al-Karak, Jordan”, in a very professional and easy way. This journal is one of outstanding medical journal.
Dear Hao Jiang, to Journal of Nutrition and Food Processing We greatly appreciate the efficient, professional and rapid processing of our paper by your team. If there is anything else we should do, please do not hesitate to let us know. On behalf of my co-authors, we would like to express our great appreciation to editor and reviewers.
As an author who has recently published in the journal "Brain and Neurological Disorders". I am delighted to provide a testimonial on the peer review process, editorial office support, and the overall quality of the journal. The peer review process at Brain and Neurological Disorders is rigorous and meticulous, ensuring that only high-quality, evidence-based research is published. The reviewers are experts in their fields, and their comments and suggestions were constructive and helped improve the quality of my manuscript. The review process was timely and efficient, with clear communication from the editorial office at each stage. The support from the editorial office was exceptional throughout the entire process. The editorial staff was responsive, professional, and always willing to help. They provided valuable guidance on formatting, structure, and ethical considerations, making the submission process seamless. Moreover, they kept me informed about the status of my manuscript and provided timely updates, which made the process less stressful. The journal Brain and Neurological Disorders is of the highest quality, with a strong focus on publishing cutting-edge research in the field of neurology. The articles published in this journal are well-researched, rigorously peer-reviewed, and written by experts in the field. The journal maintains high standards, ensuring that readers are provided with the most up-to-date and reliable information on brain and neurological disorders. In conclusion, I had a wonderful experience publishing in Brain and Neurological Disorders. The peer review process was thorough, the editorial office provided exceptional support, and the journal's quality is second to none. I would highly recommend this journal to any researcher working in the field of neurology and brain disorders.
Dear Agrippa Hilda, Journal of Neuroscience and Neurological Surgery, Editorial Coordinator, I trust this message finds you well. I want to extend my appreciation for considering my article for publication in your esteemed journal. I am pleased to provide a testimonial regarding the peer review process and the support received from your editorial office. The peer review process for my paper was carried out in a highly professional and thorough manner. The feedback and comments provided by the authors were constructive and very useful in improving the quality of the manuscript. This rigorous assessment process undoubtedly contributes to the high standards maintained by your journal.
International Journal of Clinical Case Reports and Reviews. I strongly recommend to consider submitting your work to this high-quality journal. The support and availability of the Editorial staff is outstanding and the review process was both efficient and rigorous.
Thank you very much for publishing my Research Article titled “Comparing Treatment Outcome Of Allergic Rhinitis Patients After Using Fluticasone Nasal Spray And Nasal Douching" in the Journal of Clinical Otorhinolaryngology. As Medical Professionals we are immensely benefited from study of various informative Articles and Papers published in this high quality Journal. I look forward to enriching my knowledge by regular study of the Journal and contribute my future work in the field of ENT through the Journal for use by the medical fraternity. The support from the Editorial office was excellent and very prompt. I also welcome the comments received from the readers of my Research Article.
Dear Erica Kelsey, Editorial Coordinator of Cancer Research and Cellular Therapeutics Our team is very satisfied with the processing of our paper by your journal. That was fast, efficient, rigorous, but without unnecessary complications. We appreciated the very short time between the submission of the paper and its publication on line on your site.
I am very glad to say that the peer review process is very successful and fast and support from the Editorial Office. Therefore, I would like to continue our scientific relationship for a long time. And I especially thank you for your kindly attention towards my article. Have a good day!
"We recently published an article entitled “Influence of beta-Cyclodextrins upon the Degradation of Carbofuran Derivatives under Alkaline Conditions" in the Journal of “Pesticides and Biofertilizers” to show that the cyclodextrins protect the carbamates increasing their half-life time in the presence of basic conditions This will be very helpful to understand carbofuran behaviour in the analytical, agro-environmental and food areas. We greatly appreciated the interaction with the editor and the editorial team; we were particularly well accompanied during the course of the revision process, since all various steps towards publication were short and without delay".
I would like to express my gratitude towards you process of article review and submission. I found this to be very fair and expedient. Your follow up has been excellent. I have many publications in national and international journal and your process has been one of the best so far. Keep up the great work.
We are grateful for this opportunity to provide a glowing recommendation to the Journal of Psychiatry and Psychotherapy. We found that the editorial team were very supportive, helpful, kept us abreast of timelines and over all very professional in nature. The peer review process was rigorous, efficient and constructive that really enhanced our article submission. The experience with this journal remains one of our best ever and we look forward to providing future submissions in the near future.
I am very pleased to serve as EBM of the journal, I hope many years of my experience in stem cells can help the journal from one way or another. As we know, stem cells hold great potential for regenerative medicine, which are mostly used to promote the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. I think Stem Cell Research and Therapeutics International is a great platform to publish and share the understanding towards the biology and translational or clinical application of stem cells.
I would like to give my testimony in the support I have got by the peer review process and to support the editorial office where they were of asset to support young author like me to be encouraged to publish their work in your respected journal and globalize and share knowledge across the globe. I really give my great gratitude to your journal and the peer review including the editorial office.
I am delighted to publish our manuscript entitled "A Perspective on Cocaine Induced Stroke - Its Mechanisms and Management" in the Journal of Neuroscience and Neurological Surgery. The peer review process, support from the editorial office, and quality of the journal are excellent. The manuscripts published are of high quality and of excellent scientific value. I recommend this journal very much to colleagues.
Dr.Tania Muñoz, My experience as researcher and author of a review article in The Journal Clinical Cardiology and Interventions has been very enriching and stimulating. The editorial team is excellent, performs its work with absolute responsibility and delivery. They are proactive, dynamic and receptive to all proposals. Supporting at all times the vast universe of authors who choose them as an option for publication. The team of review specialists, members of the editorial board, are brilliant professionals, with remarkable performance in medical research and scientific methodology. Together they form a frontline team that consolidates the JCCI as a magnificent option for the publication and review of high-level medical articles and broad collective interest. I am honored to be able to share my review article and open to receive all your comments.
“The peer review process of JPMHC is quick and effective. Authors are benefited by good and professional reviewers with huge experience in the field of psychology and mental health. The support from the editorial office is very professional. People to contact to are friendly and happy to help and assist any query authors might have. Quality of the Journal is scientific and publishes ground-breaking research on mental health that is useful for other professionals in the field”.
Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.
Clinical Cardiology and Cardiovascular Interventions I testity the covering of the peer review process, support from the editorial office, and quality of the journal.
