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      The Role of Mitochondrial Dysfunction in the Progression of Alzheimer’s Disease

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          Abstract

          The current molecular understanding of Alzheimer’s disease (AD) has still not re-sulted in successful interventions. Mitochondrial dysfunction of the AD brain is currently emerging as a hallmark of this disease. One mitochondrial function often affected in AD is oxidative phosphorylation responsible for ATP production, but also for production of reactive oxygen species (ROS) and for the de novo synthesis of pyrimidines. This paper reviews the role of mitochondrial produced ROS and pyrimidines in the aetiology of AD and their pro-posed role in oxidative degeneration of macromolecules, synthesis of essential phospholipids and maintenance of mitochondrial viability in the AD brain.

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          Impaired balance of mitochondrial fission and fusion in Alzheimer's disease.

          Xinglong Wang, Bo Su, Hyoung-gon Lee … (2009)
          Mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD) neurons. In this study, we explored the involvement of an abnormal mitochondrial dynamics by investigating the changes in the expression of mitochondrial fission and fusion proteins in AD brain and the potential cause and consequence of these changes in neuronal cells. We found that mitochondria were redistributed away from axons in the pyramidal neurons of AD brain. Immunoblot analysis revealed that levels of DLP1 (also referred to as Drp1), OPA1, Mfn1, and Mfn2 were significantly reduced whereas levels of Fis1 were significantly increased in AD. Despite their differential effects on mitochondrial morphology, manipulations of these mitochondrial fission and fusion proteins in neuronal cells to mimic their expressional changes in AD caused a similar abnormal mitochondrial distribution pattern, such that mitochondrial density was reduced in the cell periphery of M17 cells or neuronal process of primary neurons and correlated with reduced spine density in the neurite. Interestingly, oligomeric amyloid-beta-derived diffusible ligands (ADDLs) caused mitochondrial fragmentation and reduced mitochondrial density in neuronal processes. More importantly, ADDL-induced synaptic change (i.e., loss of dendritic spine and postsynaptic density protein 95 puncta) correlated with abnormal mitochondrial distribution. DLP1 overexpression, likely through repopulation of neuronal processes with mitochondria, prevented ADDL-induced synaptic loss, suggesting that abnormal mitochondrial dynamics plays an important role in ADDL-induced synaptic abnormalities. Based on these findings, we suggest that an altered balance in mitochondrial fission and fusion is likely an important mechanism leading to mitochondrial and neuronal dysfunction in AD brain.
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            Repair of oxidative damage to DNA: enzymology and biology.

            B Demple, L. Harrison (1994)
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              Oxidative stress hypothesis in Alzheimer's disease.

              W Markesbery (1997)
              The major hurdle in understanding Alzheimer's disease (AD) is a lack of knowledge about the etiology and pathogenesis of selective neuron death. In recent years, considerable data have accrued indicating that the brain in AD is under increased oxidative stress and this may have a role in the pathogenesis of neuron degeneration and death in this disorder. The direct evidence supporting increased oxidative stress in AD is: (1) increased brain Fe, Al, and Hg in AD, capable of stimulating free radical generation; (2) increased lipid peroxidation and decreased polyunsaturated fatty acids in the AD brain, and increased 4-hydroxynonenal, an aldehyde product of lipid peroxidation in AD ventricular fluid; (3) increased protein and DNA oxidation in the AD brain; (4) diminished energy metabolism and decreased cytochrome c oxidase in the brain in AD; (5) advanced glycation end products (AGE), malondialdehyde, carbonyls, peroxynitrite, heme oxygenase-1 and SOD-1 in neurofibrillary tangles and AGE, heme oxygenase-1, SOD-1 in senile plaques; and (6) studies showing that amyloid beta peptide is capable of generating free radicals. Supporting indirect evidence comes from a variety of in vitro studies showing that free radicals are capable of mediating neuron degeneration and death. Overall, these studies indicate that free radicals are possibly involved in the pathogenesis of neuron death in AD. Because tissue injury itself can induce reactive oxygen species (ROS) generation, it is not known whether this is a primary or secondary event. Even if free radical generation is secondary to other initiating causes, they are deleterious and part of a cascade of events that can lead to neuron death, suggesting that therapeutic efforts aimed at removal of ROS or prevention of their formation may be beneficial in AD.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Curr Med Chem
                Journal ID (iso-abbrev): Curr. Med. Chem
                Journal ID (publisher-id): CMC
                Title: Current Medicinal Chemistry
                Publisher: Bentham Science Publishers
                ISSN (Print): 0929-8673
                ISSN (Electronic): 1875-533X
                Publication date (Electronic): December 2018
                Publication date (Print): December 2018
                Volume: 25
                Issue: 40
                Pages: 5578-5587
                Affiliations
                Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen , Denmark; Healthy Brain Aging Centre (HBAC), Department of Microbiology, Oslo University Hospital , Oslo, , Norway
                Author notes
                [* ]Address correspondence to this author at the Center for Healthy Aging, Denmark; E-mail: lenera@ 123456sund.ku.dk
                Article
                Publisher ID: CMC-25-5578
                DOI: 10.2174/0929867324666170616110111
                PMC ID: 6446443
                PubMed ID: 28618998
                SO-VID: 515580e6-7838-4754-b2f9-713c4eeb7b2c
                Copyright © © 2018 Bentham Science Publishers
                License:

                This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) ( https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

                History
                Date received : 24 December 2016
                Date revision received : 02 January 2017
                Date accepted : 02 January 2017
                Categories
                Subject: Article

                ScienceOpen disciplines: Pharmaceutical chemistry
                Keywords: mitochondria,dna repair,dntp pools,nucleotide metabolism,brain
                Data availability:
                ScienceOpen disciplines: Pharmaceutical chemistry
                Keywords: mitochondria, dna repair, dntp pools, nucleotide metabolism, brain

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