Relationships Between Mitochondria and Neuroinflammation: Implications for Alzheimer's Disease.

Mitochondrial dysfunction and neuroinflammation occur in Alzheimer's disease (AD). The causes of these pathologic lesions remain uncertain, but links between these phenomena are increasingly recognized. In this review, we discuss data that indicate mitochondria or mitochondrial components may contribute to neuroinflammation. While mitochondrial dysfunction could cause neuroinflammation, neuroinflammation could also cause mitochondrial dysfunction. However, based on the systemic nature of AD mitochondrial dysfunction as well as data from experiments we discuss, the former possibility is perhaps more likely. If correct, then manipulation of mitochondria, either directly or through manipulations of bioenergetic pathways, could prove effective in reducing metabolic dysfunction and neuroinflammation in AD patients. We also review some potential approaches through which such manipulations may be achieved.

[1]  R. Swerdlow,et al.  Mitochondrial abnormalities in cybrid cell models of sporadic Alzheimer's disease worsen with passage in culture , 2004, Neurobiology of Disease.

[2]  P. Mohanan,et al.  Effect of alpha-ketoglutarate and oxaloacetate on brain mitochondrial DNA damage and seizures induced by kainic acid in mice. , 2003, Toxicology letters.

[3]  K. Davies,et al.  Polynucleotide degradation during early stage response to oxidative stress is specific to mitochondria. , 2000, Free radical biology & medicine.

[4]  I. Santana,et al.  Mitochondria dysfunction of Alzheimer's disease cybrids enhances Aβ toxicity , 2004, Journal of neurochemistry.

[5]  D. Crawford,et al.  Degraded mitochondrial DNA is a newly identified subtype of the damage associated molecular pattern (DAMP) family and possible trigger of neurodegeneration. , 2012, Journal of Alzheimer's disease : JAD.

[6]  Michael S. McGrath,et al.  Systemic immune system alterations in early stages of Alzheimer's disease , 2013, Journal of Neuroimmunology.

[7]  K. Gomes,et al.  Increased plasma levels of BDNF and inflammatory markers in Alzheimer's disease. , 2014, Journal of psychiatric research.

[8]  R. Swerdlow,et al.  Effect of one month duration ketogenic and non-ketogenic high fat diets on mouse brain bioenergetic infrastructure , 2015, Journal of Bioenergetics and Biomembranes.

[9]  R. Swerdlow,et al.  The Alzheimer's disease mitochondrial cascade hypothesis: progress and perspectives. , 2014, Biochimica et biophysica acta.

[10]  John X. Morris,et al.  Increased risk of dementia in mothers of Alzheimer's disease cases , 1996, Neurology.

[11]  Michael Stumvoll,et al.  Antioxidants prevent health-promoting effects of physical exercise in humans , 2009, Proceedings of the National Academy of Sciences.

[12]  Roger N Gunn,et al.  In-vivo measurement of activated microglia in dementia , 2001, The Lancet.

[13]  Y. Smith,et al.  Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet , 2006, Annals of neurology.

[14]  Fred H. Gage,et al.  Exercise Enhances Learning and Hippocampal Neurogenesis in Aged Mice , 2005, The Journal of Neuroscience.

[15]  J. Davis,et al.  Exercise training increases mitochondrial biogenesis in the brain. , 2011, Journal of applied physiology.

[16]  J. Kaye,et al.  The aging systemic milieu negatively regulates neurogenesis and cognitive function , 2011, Nature.

[17]  A. Navarro,et al.  Beneficial effects of moderate exercise on mice aging: survival, behavior, oxidative stress, and mitochondrial electron transfer. , 2004, American journal of physiology. Regulatory, integrative and comparative physiology.

[18]  Sarah A. Stern,et al.  Astrocyte-Neuron Lactate Transport Is Required for Long-Term Memory Formation , 2011, Cell.

[19]  I. Sinelnikov,et al.  Effect of Glutamate and Blood Glutamate Scavengers Oxaloacetate and Pyruvate on Neurological Outcome and Pathohistology of the Hippocampus after Traumatic Brain Injury in Rats , 2012, Anesthesiology.

[20]  C. Bondy,et al.  A ketogenic diet increases brain insulin-like growth factor receptor and glucose transporter gene expression. , 2003, Endocrinology.

[21]  R. Swerdlow Mitochondria and cell bioenergetics: increasingly recognized components and a possible etiologic cause of Alzheimer's disease. , 2012, Antioxidants & redox signaling.

[22]  R. Swerdlow Mitochondrial Medicine and the Neurodegenerative Mitochondriopathies , 2009, Pharmaceuticals.

[23]  J. Sastre,et al.  Oral administration of vitamin C decreases muscle mitochondrial biogenesis and hampers training-induced adaptations in endurance performance. , 2008, The American journal of clinical nutrition.

[24]  R. Swerdlow,et al.  Cytoplasmic hybrid (cybrid) cell lines as a practical model for mitochondriopathies , 2014, Redox biology.

[25]  J. Cross,et al.  The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial , 2008, The Lancet Neurology.

[26]  R. Swerdlow Bioenergetic medicine , 2014, British journal of pharmacology.

[27]  E. Crouser,et al.  Mitochondrial Transcription Factor A Serves as a Danger Signal by Augmenting Plasmacytoid Dendritic Cell Responses to DNA , 2012, The Journal of Immunology.

[28]  H. Akiyama,et al.  Inflammatory response in Alzheimer's disease. , 1994, The Tohoku journal of experimental medicine.

[29]  L. Guarente,et al.  Nicotinamide adenine dinucleotide, a metabolic regulator of transcription, longevity and disease. , 2003, Current opinion in cell biology.

[30]  R Luft,et al.  The development of mitochondrial medicine. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[31]  D. Hood Mechanisms of exercise-induced mitochondrial biogenesis in skeletal muscle. , 2009, Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme.

[32]  L. Costantini,et al.  Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer's disease: a randomized, double-blind, placebo-controlled, multicenter trial , 2009, Nutrition & metabolism.

[33]  Pierre J Magistretti,et al.  In Vivo Evidence for Lactate as a Neuronal Energy Source , 2011, The Journal of Neuroscience.

[34]  C. Plata-salamán,et al.  Inflammation and Alzheimer’s disease , 2000, Neurobiology of Aging.

[35]  W. Brooks,et al.  Alternate day fasting impacts the brain insulin‐signaling pathway of young adult male C57BL/6 mice , 2011, Journal of neurochemistry.

[36]  C. Filley,et al.  Cytochrome oxidase deficiency in Alzheimer's disease , 1990, Neurology.

[37]  R. Swerdlow,et al.  Bioenergetic Dysfunction and Inflammation in Alzheimer’s Disease: A Possible Connection , 2014, Front. Aging Neurosci..

[38]  Gabriele Siciliano,et al.  Cytochrome c oxidase and mitochondrial F1F0-ATPase (ATP synthase) activities in platelets and brain from patients with Alzheimer’s disease , 2002, Neurobiology of Aging.

[39]  Rachel L. Mistur,et al.  FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer’s disease , 2009, European Journal of Nuclear Medicine and Molecular Imaging.

[40]  M. Atalay,et al.  Exercise alters SIRT1, SIRT6, NAD and NAMPT levels in skeletal muscle of aged rats , 2010, Mechanisms of Ageing and Development.

[41]  Walter J Koroshetz,et al.  Plasma biomarkers associated with the apolipoprotein E genotype and Alzheimer disease. , 2012, Archives of neurology.

[42]  David L Wilson,et al.  Overexpression of the Cytosolic Form of Phosphoenolpyruvate Carboxykinase (GTP) in Skeletal Muscle Repatterns Energy Metabolism in the Mouse*♦ , 2007, Journal of Biological Chemistry.

[43]  J. Bennett,et al.  Endogenous oxidative stress in sporadic Alzheimer's disease neuronal cybrids reduces viability by increasing apoptosis through pro-death signaling pathways and is mimicked by oxidant exposure of control cybrids , 2005, Neurobiology of Disease.

[44]  D. Clegg,et al.  Dietary ketosis enhances memory in mild cognitive impairment , 2012, Neurobiology of Aging.

[45]  C. Cotman,et al.  Exercise: a behavioral intervention to enhance brain health and plasticity , 2002, Trends in Neurosciences.

[46]  A. Navarro,et al.  Systemic and mitochondrial adaptive responses to moderate exercise in rodents. , 2008, Free radical biology & medicine.

[47]  B. Mohar,et al.  Blood glutamate scavengers prolong the survival of rats and mice with brain-implanted gliomas , 2012, Investigational New Drugs.

[48]  A. Simmons,et al.  Inflammatory Proteins in Plasma Are Associated with Severity of Alzheimer’s Disease , 2013, PloS one.

[49]  R. Swerdlow,et al.  Mitochondrial lysates induce inflammation and Alzheimer's disease-relevant changes in microglial and neuronal cells. , 2015, Journal of Alzheimer's disease : JAD.

[50]  R. Swerdlow,et al.  Lactate administration reproduces specific brain and liver exercise‐related changes , 2013, Journal of neurochemistry.

[51]  P. Huttenlocher Ketonemia and Seizures: Metabolic and Anticonvulsant Effects of Two Ketogenic Diets in Childhood Epilepsy , 1976, Pediatric Research.

[52]  M. Reger,et al.  Effects of β-hydroxybutyrate on cognition in memory-impaired adults , 2004, Neurobiology of Aging.

[53]  P. Calabresi,et al.  Mitochondria and the link between neuroinflammation and neurodegeneration. , 2010, Journal of Alzheimer's disease : JAD.

[54]  C. Hong,et al.  Peripheral Cytokines and Chemokines in Alzheimer’s Disease , 2009, Dementia and Geriatric Cognitive Disorders.

[55]  J. Tschopp,et al.  A role for mitochondria in NLRP3 inflammasome activation , 2011, Nature.

[56]  G. López-Castejón,et al.  NLRP3-Inflammasome Activating DAMPs Stimulate an Inflammatory Response in Glia in the Absence of Priming Which Contributes to Brain Inflammation after Injury , 2012, Front. Immun..

[57]  Eric Achten,et al.  Assessment of Neuroinflammation and Microglial Activation in Alzheimer’s Disease with Radiolabelled PK11195 and Single Photon Emission Computed Tomography , 2003, European Neurology.

[58]  R. Swerdlow,et al.  Effect of exercise on mouse liver and brain bioenergetic infrastructures , 2013, Experimental physiology.

[59]  E. Crouser,et al.  Monocyte activation by necrotic cells is promoted by mitochondrial proteins and formyl peptide receptors , 2009, Critical care medicine.

[60]  R. Swerdlow Role and treatment of mitochondrial DNA-related mitochondrial dysfunction in sporadic neurodegenerative diseases. , 2011, Current pharmaceutical design.

[61]  K. Yoshikawa Studies on Anti-diabetic Effect of Sodium Oxalcacetate , 1968 .

[62]  K. Krause,et al.  Chemokine receptors in the central nervous system: role in brain inflammation and neurodegenerative diseases , 2005, Brain Research Reviews.

[63]  H. Möller,et al.  A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients , 2000, Neurobiology of Aging.

[64]  Magda I. Mohamad,et al.  Histone Deacetylases Enzyme, Copper, and IL-8 Levels in Patients With Alzheimer’s Disease , 2013, American journal of Alzheimer's disease and other dementias.

[65]  T. Sobrino,et al.  Oxaloacetate: a novel neuroprotective for acute ischemic stroke. , 2012, The international journal of biochemistry & cell biology.

[66]  Rachel L. Mistur,et al.  Maternal family history of Alzheimer's disease predisposes to reduced brain glucose metabolism , 2007, Proceedings of the National Academy of Sciences.

[67]  W. Brooks,et al.  Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis. , 2014, Human molecular genetics.

[68]  Pierre J Magistretti,et al.  Neuroenergetics: Calling Upon Astrocytes to Satisfy Hungry Neurons , 2004, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[69]  R. Swerdlow,et al.  Effect of high-intensity exercise on aged mouse brain mitochondria, neurogenesis, and inflammation , 2014, Neurobiology of Aging.

[70]  R. Swerdlow,et al.  A "mitochondrial cascade hypothesis" for sporadic Alzheimer's disease. , 2004, Medical hypotheses.

[71]  N. Herrmann,et al.  A Meta-Analysis of Cytokines in Alzheimer's Disease , 2010, Biological Psychiatry.

[72]  Nathan A. Bihlmeyer,et al.  Transcellular degradation of axonal mitochondria , 2014, Proceedings of the National Academy of Sciences.

[73]  H. Akiyama,et al.  Cell mediators of inflammation in the Alzheimer disease brain. , 2000, Alzheimer disease and associated disorders.

[74]  J. Holloszy Adaptation of skeletal muscle to endurance exercise. , 1975, Medicine and science in sports.

[75]  R. Swerdlow,et al.  Bioenergetic flux, mitochondrial mass and mitochondrial morphology dynamics in AD and MCI cybrid cell lines. , 2013, Human molecular genetics.

[76]  R. Honea,et al.  Maternal family history is associated with Alzheimer's disease biomarkers. , 2012, Journal of Alzheimer's disease : JAD.

[77]  R. Swerdlow,et al.  Alzheimer's disease cybrids replicate β‐amyloid abnormalities through cell death pathways , 2000 .

[78]  D. Walker,et al.  Mitochondrial transcription factor A (Tfam) is a pro-inflammatory extracellular signaling molecule recognized by brain microglia , 2014, Molecular and Cellular Neuroscience.

[79]  Tanja Diemer,et al.  Oxaloacetate supplementation increases lifespan in Caenorhabditis elegans through an AMPK/FOXO‐dependent pathway , 2009, Aging cell.