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Mitochondrial Dysfunction: Common Final Pathway in Brain Aging and Alzheimer’s Disease—Therapeutic Aspects

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Abstract

As a fully differentiated organ, our brain is very sensitive to cumulative oxidative damage of proteins, lipids, and DNA occurring during normal aging because of its high energy metabolism and the relative low activity of antioxidative defense mechanisms. As a major consequence, perturbations of energy metabolism including mitochondrial dysfunction, alterations of signaling mechanisms and of gene expression culminate in functional deficits. With the increasing average life span of humans, age-related cognitive disorders such as Alzheimer’s disease (AD) are a major health concern in our society. Age-related mitochondrial dysfunction underlies most neurodegenerative diseases, where it is potentiated by disease-specific factors. AD is characterized by two major histopathological hallmarks, initially intracellular and with the progression of the disease extracellular accumulation of oligomeric and fibrillar β-amyloid peptides and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. In this review, we focus on findings in AD animal and cell models indicating that these histopathological alterations induce functional deficits of the respiratory chain complexes and therefore consecutively result in mitochondrial dysfunction and oxidative stress. These parameters lead synergistically with the alterations of the brain aging process to typical signs of neurodegeneration in the later state of the disease, including synaptic dysfunction, loss of synapses and neurites, and finally neuronal loss. We suggest that mitochondrial protection and subsequent reduction of oxidative stress are important targets for prevention and long-term treatment of early stages of AD.

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Abbreviations

Aβ:

Amyloid beta

AD:

Alzheimer’s disease

APP:

Amyloid precursor protein

COX:

Cytochrome c oxidase

dG:

8-oxo-2′-Deoxyguanosine oxo8

FAD:

Familial Alzheimer’s disease

GPx:

Glutathione peroxidase

HNE:

4-Hydroxynonenal

MDA:

Malondialdehyde

Mn-SOD:

Manganese superoxide dismutase

mtDNA:

Mitochondrial DNA

PS:

Presenilin

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

SNP:

Sodium nitroprusside

References

  1. Mattson MP et al (2002) Modification of brain aging and neurodegenerative disorders by genes, diet, and behavior. Physiol Rev 82:637–672

    CAS  PubMed  Google Scholar 

  2. Mattson MP, Magnus T (2006) Ageing and neuronal vulnerability. Nat Rev Neurosci 7:278–294

    CAS  PubMed  Google Scholar 

  3. Balaban RS et al (2005) Mitochondria, oxidants, and aging. Cell 120:483–495

    CAS  PubMed  Google Scholar 

  4. Benzi G et al (1992) The mitochondrial electron transfer alteration as a factor involved in the brain aging. Neurobiol Aging 13:361–368

    CAS  PubMed  Google Scholar 

  5. Moreira PI et al (2007) Alzheimer’s disease: a lesson from mitochondrial dysfunction. Antioxid Redox Signal 9:1621–1630

    CAS  PubMed  Google Scholar 

  6. Reddy PH (2007) Mitochondrial dysfunction in aging and Alzheimer’s disease: strategies to protect neurons. Antioxid Redox Signal 9:1647–1658

    CAS  PubMed  Google Scholar 

  7. Atamna H, Frey WH (2007) Mechanisms of mitochondrial dysfunction and energy deficiency in Alzheimer’s disease. Mitochondrion 7:297–310

    CAS  PubMed  Google Scholar 

  8. Lenaz G et al (1997) Mitochondrial complex I defects in aging. Mol Cell Biochem 174:329–333

    CAS  PubMed  Google Scholar 

  9. Leuner K et al (2007) Mitochondrial dysfunction: the first domino in brain aging and Alzheimer’s disease? Antioxid Redox Signal 9:1659–1675

    CAS  PubMed  Google Scholar 

  10. Martinez M et al (1994) Age-related changes in glutathione and lipid peroxide content in mouse synaptic mitochondria: relationship to cytochrome c oxidase decline. Neurosci Lett 170:121–124

    CAS  PubMed  Google Scholar 

  11. Richter C et al (1988) Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci USA 85:6465–6467

    CAS  PubMed  Google Scholar 

  12. Wozniak A et al (2004) Activity of antioxidant enzymes and concentration of lipid peroxidation products in selected tissues of mice of different ages, both healthy and melanoma-bearing. Z Gerontol Geriatr 37:184–189

    CAS  PubMed  Google Scholar 

  13. Schmitt-Schillig S et al (2005) Flavonoids and the aging brain. J Physiol Pharmacol 56(Suppl 1):23–36

    PubMed  Google Scholar 

  14. Schaffer S et al (2006) Plant foods and brain aging: a critical appraisal. Forum Nutr 59:86–115

    CAS  PubMed  Google Scholar 

  15. Harper ME et al (2004) Ageing, oxidative stress, and mitochondrial uncoupling. Acta Physiol Scand 182:321–331

    CAS  PubMed  Google Scholar 

  16. Nunomura A et al (2001) Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 60:759–767

    CAS  PubMed  Google Scholar 

  17. Nunomura A et al (2006) Involvement of oxidative stress in Alzheimer disease. J Neuropathol Exp Neurol 65:631–641

    CAS  PubMed  Google Scholar 

  18. Coyle JT, Puttfarcken P (1993) Oxidative stress, glutamate, and neurodegenerative disorders. Science 262:689–695

    CAS  PubMed  Google Scholar 

  19. Floyd RA, Hensley K (2002) Oxidative stress in brain aging. Implications for therapeutics of neurodegenerative diseases. Neurobiol Aging 23:795–807

    CAS  PubMed  Google Scholar 

  20. Leutner S et al (2001) ROS generation, lipid peroxidation and antioxidant enzyme activities in the aging brain. J Neural Transm 108:955–967

    CAS  PubMed  Google Scholar 

  21. Mattson MP et al (2008) Mitochondria in neuroplasticity and neurological disorders. Neuron 60:748–766

    CAS  PubMed  Google Scholar 

  22. Selkoe DJ (2008) Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav Brain Res 192:106–113

    CAS  PubMed  Google Scholar 

  23. Lacor PN et al (2007) Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci 27:796–807

    CAS  PubMed  Google Scholar 

  24. Hirai K et al (2001) Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci 21:3017–3023

    CAS  PubMed  Google Scholar 

  25. Manczak M et al (2004) Differential expression of oxidative phosphorylation genes in patients with Alzheimer’s disease: implications for early mitochondrial dysfunction and oxidative damage. Neuromolecular Med 5:147–162

    CAS  PubMed  Google Scholar 

  26. Manczak M et al (2006) Mitochondria are a direct site of A beta accumulation in Alzheimer’s disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet 15:1437–1449

    CAS  PubMed  Google Scholar 

  27. Valla J et al (2001) Energy hypometabolism in posterior cingulate cortex of Alzheimer’s patients: superficial laminar cytochrome oxidase associated with disease duration. J Neurosci 21:4923–4930

    CAS  PubMed  Google Scholar 

  28. Mosconi L et al (2008) Brain glucose hypometabolism and oxidative stress in preclinical Alzheimer’s disease. Ann N Y Acad Sci 1147:180–195

    Article  CAS  PubMed  Google Scholar 

  29. Casley CS et al (2002) beta-Amyloid inhibits integrated mitochondrial respiration and key enzyme activities. J Neurochem 80:91–100

    CAS  PubMed  Google Scholar 

  30. Cardoso SM et al (2004) Cytochrome c oxidase is decreased in Alzheimer’s disease platelets. Neurobiol Aging 25:105–110

    CAS  PubMed  Google Scholar 

  31. Kish SJ et al (1992) Brain cytochrome oxidase in Alzheimer’s disease. J Neurochem 59:776–779

    CAS  PubMed  Google Scholar 

  32. Cottrell DA et al (2002) The role of cytochrome c oxidase deficient hippocampal neurones in Alzheimer’s disease. Neuropathol Appl Neurobiol 28:390–396

    CAS  PubMed  Google Scholar 

  33. Mutisya EM et al (1994) Cortical cytochrome oxidase activity is reduced in Alzheimer’s disease. J Neurochem 63:2179–2184

    CAS  PubMed  Google Scholar 

  34. Hauptmann S et al (2009) Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice. Neurobiol Aging 30:1574–1586

    CAS  PubMed  Google Scholar 

  35. Blanchard V et al (2003) Time sequence of maturation of dystrophic neurites associated with A beta deposits in APP/PS1 transgenic mice. Exp Neurol 184:247–263

    CAS  PubMed  Google Scholar 

  36. Caspersen C et al (2005) Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer’s disease. FASEB J 19:2040–2041

    CAS  PubMed  Google Scholar 

  37. Aleardi AM et al (2005) Gradual alteration of mitochondrial structure and function by beta-amyloids: importance of membrane viscosity changes, energy deprivation, reactive oxygen species production, and cytochrome c release. J Bioenerg Biomembr 37:207–225

    CAS  PubMed  Google Scholar 

  38. Chong ZZ et al (2005) Oxidative stress in the brain: novel cellular targets that govern survival during neurodegenerative disease. Progr Neurobiol 75:207–246

    CAS  Google Scholar 

  39. Butterfield DA et al (2006) Redox proteomics identification of oxidatively modified brain proteins in inherited Alzheimer’s disease: an initial assessment. J Alzheimers Dis 10:391–397

    CAS  PubMed  Google Scholar 

  40. Campion D et al (1995) Mutations of the Presenilin-I gene in families with early-onset Alzheimers-disease. Hum Mol Genet 4:2373–2377

    CAS  PubMed  Google Scholar 

  41. Lleo A et al (2004) Clinical, pathological, and biochemical spectrum of Alzheimer disease associated with PS-1 mutations. Am J Geriatr Psychiatry 12:146–156

    PubMed  Google Scholar 

  42. Velez-Pardo C et al (2001) Ultrastructure evidence of necrotic neural cell death in familial Alzheimer’s disease brains bearing presenilin-1 E280A mutation. J Alzheimers Dis 3:409–415

    PubMed  Google Scholar 

  43. Keller JN et al (1998) Mitochondrial manganese superoxide dismutase prevents neural apoptosis and reduces ischemic brain injury: suppression of peroxynitrite production, lipid peroxidation, and mitochondrial dysfunction. J Neurosci 18:687–697

    CAS  PubMed  Google Scholar 

  44. Zorov DB et al (2009) Regulation and pharmacology of the mitochondrial permeability transition pore. Cardiovasc Res 83:213–225

    CAS  PubMed  Google Scholar 

  45. Hansson Petersen CA et al (2008) The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae. Proc Natl Acad Sci USA 105:13145–13150

    CAS  PubMed  Google Scholar 

  46. Lustbader JW et al (2004) ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease. Science 304:448–452

    CAS  PubMed  Google Scholar 

  47. Anandatheerthavarada HK et al (2003) Mitochondrial targeting and a novel transmembrane arrest of Alzheimer’s amyloid precursor protein impairs mitochondrial function in neuronal cells. J Cell Biol 161:41–54

    CAS  PubMed  Google Scholar 

  48. Devi L et al (2006) Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer’s disease brain is associated with mitochondrial dysfunction. J Neurosci 26:9057–9068

    CAS  PubMed  Google Scholar 

  49. Pavlov PF et al (2009) Mitochondrial accumulation of APP and Abeta: significance for Alzheimer disease pathogenesis. J Cell Mol Med 13:4137–4145

    Google Scholar 

  50. Wang X et al (2008) Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci USA 105:19318–19323

    CAS  PubMed  Google Scholar 

  51. Wang X et al (2009) Impaired balance of mitochondrial fission and fusion in Alzheimer’s disease. J Neurosci 29:9090–9103

    CAS  PubMed  Google Scholar 

  52. Cho DH et al (2009) S-Nitrosylation of Drp1 mediates beta-Amyloid-related mitochondrial fission and neuronal injury. Science 324:102–105

    CAS  PubMed  Google Scholar 

  53. Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362:329–344

    CAS  PubMed  Google Scholar 

  54. David DC et al (2005) Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L Tau transgenic mice. J Biol Chem 280:23802–23814

    CAS  PubMed  Google Scholar 

  55. Gotz J et al (2001) Tau filament formation in transgenic mice expressing P301L tau. J Biol Chem 276:529–534

    CAS  PubMed  Google Scholar 

  56. Gotz J et al (2001) Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293:1491–1495

    CAS  PubMed  Google Scholar 

  57. Rhein V et al (2009) Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer’s disease mice. Proc Natl Acad Sci USA 106:20057–20062

    CAS  PubMed  Google Scholar 

  58. Yao J et al (2009) Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in female mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 106:14670–14675

    CAS  PubMed  Google Scholar 

  59. Halliwell B (2006) Oxidative stress and neurodegeneration: where are we now? J Neurochem 97:1634–1658

    CAS  PubMed  Google Scholar 

  60. Culmsee C, Landshamer S (2006) Molecular insights into mechanisms of the cell death program: role in the progression of neurodegenerative disorders. Curr Alzheimer Res 3:269–283

    CAS  PubMed  Google Scholar 

  61. Mattson MP (2004) Pathways towards and away from Alzheimer’s disease. Nature 430:631–639

    CAS  PubMed  Google Scholar 

  62. Perry G et al (2000) Oxidative damage in Alzheimer’s disease: the metabolic dimension. Int J Dev Neurosci 18:417–421

    CAS  PubMed  Google Scholar 

  63. Richartz E et al (2002) Increased serum levels of CD95 in Alzheimer’s disease. Dement Geriatr Cogn Disord 13:178–182

    CAS  PubMed  Google Scholar 

  64. Zarkovic K (2003) 4-Hydroxynonenal and neurodegenerative diseases. Mol Aspects Med 24:293–303

    CAS  PubMed  Google Scholar 

  65. Schuessel K et al (2006) Aging sensitizes toward ROS formation and lipid peroxidation in PS1M146L transgenic mice. Free Radic Biol Med 40:850–862

    CAS  PubMed  Google Scholar 

  66. Aksenov MY et al (1998) The expression of key oxidative stress-handling genes in different brain regions in Alzheimer’s disease. J Mol Neurosci 11:151–164

    CAS  PubMed  Google Scholar 

  67. Newman SF et al (2007) An increase in S-glutathionylated proteins in the Alzheimer’s disease inferior parietal lobule, a proteomics approach. J Neurosci Res 85:1506–1514

    CAS  PubMed  Google Scholar 

  68. Sultana R et al (2006) Redox proteomics identification of oxidized proteins in Alzheimer’s disease hippocampus and cerebellum: an approach to understand pathological and biochemical alterations in AD. Neurobiol Aging 27:1564–1576

    CAS  PubMed  Google Scholar 

  69. Sultana R et al (2006) Protein oxidation and lipid peroxidation in brain of subjects with Alzheimer’s disease: insights into mechanism of neuro degeneration from redox proteomics. Antiox Redox Signal 8:2021–2037

    CAS  Google Scholar 

  70. Keller JN et al (2005) Evidence of increased oxidative damage in subjects with mild cognitive impairment. Neurology 64:1152–1156

    CAS  PubMed  Google Scholar 

  71. Migliore L et al (2005) Oxidative DNA damage in peripheral leukocytes of mild cognitive impairment and AD patients. Neurobiol Aging 26:567–573

    CAS  PubMed  Google Scholar 

  72. Pratico D et al (2001) Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J Neurosci 21:4183–4187

    CAS  PubMed  Google Scholar 

  73. Guidi I et al (2006) Oxidative imbalance in patients with mild cognitive impairment and Alzheimer’s disease. Neurobiol Aging 27:262–269

    CAS  PubMed  Google Scholar 

  74. Rinaldi P et al (2003) Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer’s disease. Neurobiol Aging 24:915–919

    CAS  PubMed  Google Scholar 

  75. Leutner S et al (2005) Enhanced ROS-generation in lymphocytes from Alzheimer’s patients. Pharmacopsychiatry 38:312–315

    CAS  PubMed  Google Scholar 

  76. Drake J et al (2003) Oxidative stress precedes fibrillar deposition of Alzheimer’s disease amyloid beta-peptide (1-42) in a transgenic Caenorhabditis elegans model. Neurobiol Aging 24:415–420

    CAS  PubMed  Google Scholar 

  77. Pratico D (2005) Peripheral biomarkers of oxidative damage in Alzheimer’s disease: the road ahead. Neurobiol Aging 26:581–583

    CAS  PubMed  Google Scholar 

  78. Schuessel K et al (2005) Impaired Cu/Zn-SOD activity contributes to increased oxidative damage in APP transgenic mice. Neurobiol Dis 18:89–99

    CAS  PubMed  Google Scholar 

  79. Abdul HM et al (2006) Mutations in amyloid precursor protein and presenilin-1 genes increase the basal oxidative stress in murine neuronal cells and lead to increased sensitivity to oxidative stress mediated by amyloid beta-peptide (1-42), H2O2 and kainic acid: implications for Alzheimer’s disease. J Neurochem 96:1322–1335

    CAS  Google Scholar 

  80. Hensley K et al (1994) A model for beta-Amyloid aggregation and neurotoxicity based on free-radical generation by the peptide—relevance to Alzheimer-disease. Proc Natl Acad Sci USA 91:3270–3274

    CAS  PubMed  Google Scholar 

  81. Hensley K et al (1995) Brain regional correspondence between Alzheimers-disease histopathology and biomarkers of protein oxidation. J Neurochem 65:2146–2156

    Article  CAS  PubMed  Google Scholar 

  82. Murray IVJ et al (2005) Promotion of oxidative lipid membrane damage by amyloid beta proteins. Biochemistry 44:12606–12613

    CAS  PubMed  Google Scholar 

  83. Keil U et al (2004) Amyloid beta-induced changes in nitric oxide production and mitochondrial activity lead to apoptosis. J Biol Chem 279:50310–50320

    CAS  PubMed  Google Scholar 

  84. Marques CA et al (2003) Neurotoxic mechanisms caused by the Alzheimer’s disease-linked Swedish amyloid precursor protein mutation—oxidative stress, caspases, and the JNK pathway. J Biol Chem 278:28294–28302

    CAS  PubMed  Google Scholar 

  85. Opazo C et al (2002) Metalloenzyme-like activity of Alzheimer’s disease beta-amyloid. Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H(2)O(2). J Biol Chem 277:40302–40308

    CAS  PubMed  Google Scholar 

  86. Newman M et al (2007) Alzheimer disease: amyloidogenesis, the presenilins and animal models. Biochim Biophys Acta 1772:285–297

    CAS  PubMed  Google Scholar 

  87. Hauptmann S et al (2006) Mitochondrial dysfunction in sporadic and genetic Alzheimer’s disease. Exp Gerontol 41:668–673

    CAS  PubMed  Google Scholar 

  88. Keil U et al (2006) Mitochondrial dysfunction induced by disease relevant A beta PP and tau protein mutations. J Alzheimers Dis 9:139–146

    PubMed  Google Scholar 

  89. Peters I et al (2009) The interaction of beta-amyloid protein with cellular membranes stimulates its own production. Biochim Biophys Acta 1788:964–972

    CAS  PubMed  Google Scholar 

  90. Gura T (2008) Hope in Alzheimer’s fight emerges from unexpected places. Nat Med 14:894–894

    CAS  PubMed  Google Scholar 

  91. Doody RS et al (2008) Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer’s disease: a randomised, double-blind, placebo-controlled study. Lancet 372:207–215

    CAS  PubMed  Google Scholar 

  92. Bachurin SO et al (2003) Mitochondria as a target for neurotoxins and neuroprotective agents. Neuroprotective Agents 993:334–344

    CAS  Google Scholar 

  93. Bernales S et al (2008) Dimebon induces neuritic outgrowth and mitochondrial stabilization Programm No. 543.29/S12 Neuroscience Meeting Planner Washington, DC: Society for Neuroscience, Online

  94. Atamna H et al (2008) Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways. FASEB J 22:703–712

    CAS  PubMed  Google Scholar 

  95. Callaway NL et al (2002) Methylene blue restores spatial memory retention impaired by an inhibitor of cytochrome oxidase in rats. Neurosci Lett 332:83–86

    CAS  PubMed  Google Scholar 

  96. Callaway NL et al (2004) Methylene blue improves brain oxidative metabolism and memory retention in rats. Pharmacol Biochem Behav 77:175–181

    CAS  PubMed  Google Scholar 

  97. Zhao BL (2009) Natural antioxidants protect neurons in Alzheimer’s disease and Parkinson’s disease. Neurochem Res 34:630–638

    CAS  PubMed  Google Scholar 

  98. Boothby LA, Doering PL (2005) Vitamin C and vitamin E for Alzheimer’s disease. Ann Pharmacother 39:2073–2080

    CAS  PubMed  Google Scholar 

  99. Feart C et al (2009) Adherence to a Mediterranean diet, cognitive decline, and risk of dementia. JAMA 302:638–648

    CAS  PubMed  Google Scholar 

  100. Scarmeas N et al (2006) Mediterranean diet and risk for Alzheimer’s disease. Ann Neurol 59:912–921

    PubMed  Google Scholar 

  101. Scarmeas N et al (2007) Mediterranean diet (MeDi) and longevity in Alzheimer’s disease (AD) course. Neurology 68:A169–A169

    Google Scholar 

  102. Mattson MP (2008) Dietary factors, hormesis and health. Ageing Res Rev 7:43–48

    PubMed  Google Scholar 

  103. Mattson MP (2008) Hormesis and disease resistance: activation of cellular stress response pathways. Hum Exp Toxicol 27:155–162

    PubMed  Google Scholar 

  104. Abdel-Kader R et al (2007) Stabilization of mitochondrial function by Ginkgo biloba extract (EGb 761). Pharmacol Res 56:493–502

    CAS  PubMed  Google Scholar 

  105. Eckert A et al (2005) Stabilization of mitochondrial membrane potential and improvement of neuronal energy metabolism by Ginkgo biloba extract EGb 761. Ann N Y Acad Sci 1056:474–485

    PubMed  Google Scholar 

  106. Sastre J et al (1998) A Ginkgo biloba extract (EGb 761) prevents mitochondrial aging by protecting against oxidative stress. Free Radic Biol Med 24:298–304

    CAS  PubMed  Google Scholar 

  107. Janssens D et al (2000) Protection by bilobalide of the ischaemia-induced alterations of the mitochondrial respiratory activity. Fundam Clin Pharmacol 14:193–201

    CAS  PubMed  Google Scholar 

  108. Defeudis FV, Drieu K (2000) Ginkgo biloba extract (EGb 761) and CNS functions: basic studies and clinical applications. Curr Drug Targets 1:25–58

    CAS  PubMed  Google Scholar 

  109. Schindowski K et al (2001) Age-related increase of oxidative stress-induced apoptosis in mice—prevention by Ginkgo biloba extract (EGb761). J Neural Transm 108:969–978

    CAS  PubMed  Google Scholar 

  110. Wu Z et al (2002) Ginkgo biloba extract EGb 761 increases stress resistance and extends life span of Caenorhabditis elegans. Cell Mol Biol (Noisy-le-grand) 48:725–731

    CAS  Google Scholar 

  111. Bridi R et al (2001) The antioxidant activity of standardized extract of Ginkgo biloba (EGb 761) in rats. Phytother Res 15:449–451

    CAS  PubMed  Google Scholar 

  112. Smith JV, Luo Y (2003) Elevation of oxidative free radicals in Alzheimer’s disease models can be attenuated by Ginkgo biloba extract EGb 761. J Alzheimers Dis 5:287–300

    PubMed  Google Scholar 

  113. Zimmermann M et al (2002) Ginkgo biloba extract: from molecular mechanisms to the treatment of Alzheimer’s disease. Cell Mol Biol (Noisy-le-grand) 48:613–623

    CAS  Google Scholar 

  114. Gohil K, Packer L (2002) Bioflavonoid-rich botanical extracts show antioxidant and gene regulatory activity. Ann N Y Acad Sci 957:70–77

    CAS  PubMed  Google Scholar 

  115. Muller WE et al (1999) Piracetam: novelty in a unique mode of action. Pharmacopsychiatry 32:2–9

    CAS  PubMed  Google Scholar 

  116. Keil U et al (2006) Piracetam improves mitochondrial dysfunction following oxidative stress. Br J Pharmacol 147:199–208

    CAS  PubMed  Google Scholar 

  117. Kurz C et al (2010) The metabolic enhancer piracetam ameliorates β-amyloid peptide induced impairment of mitochondrial function and neuritic outgrowth. Br J Pharmacol 160:246–257

    Google Scholar 

  118. Muller WE et al (2004) Piracetam stabilizes mitochondrial function in vitro and in vivo. Neuropsychopharmacology 29:S129–S129

    Google Scholar 

  119. Benzi G et al (1985) Influence of aging and exogenous substances on cerebral energy-metabolism in posthypoglycemic recovery. Biochem Pharmacol 34:1477–1483

    CAS  PubMed  Google Scholar 

  120. Domanska-Janik K, Zaleska M (1977) The action of piracetam on 14C-glucose metabolism in normal and posthypoxic rat cerebral coretx slices. Pol J Pharmacol Pharm 29:111–116

    CAS  PubMed  Google Scholar 

  121. Heiss WD et al (1988) Effect of piracetam on cerebral glucose-metabolism in Alzheimers-disease as measured by positron emission tomography. J Cereb Blood Flow Metab 8:613–617

    CAS  PubMed  Google Scholar 

  122. Naftalin RJ et al (2004) Piracetam and TRH analogues antagonise inhibition by barbiturates, diazepam, melatonin and galanin of human erythrocyte D-glucose transport. Br J Pharmacol 142:594–608

    CAS  PubMed  Google Scholar 

  123. Guglielmotto M et al (2009) The up-regulation of BACE1 mediated by hypoxia and ischemic injury: role of oxidative stress and HIF1 alpha. J Neurochem 108:1045–1056

    CAS  PubMed  Google Scholar 

  124. Jin SM et al (2007) DNA damage-inducing agent-elicited gamma-secretase activity is dependent on Bax/Bcl-2 pathway but not on caspase cascades. Cell Death Differ 14:189–192

    CAS  PubMed  Google Scholar 

  125. Li Z et al (2004) The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 119:873–887

    CAS  PubMed  Google Scholar 

  126. Mattson MP (2007) Mitochondrial regulation of neuronal plasticity. Neurochem Res 32:707–715

    CAS  PubMed  Google Scholar 

  127. Schon EA, Manfredi G (2003) Neuronal degeneration and mitochondrial dysfunction. J Clin Invest 111:303–312

    CAS  PubMed  Google Scholar 

  128. Reddy PH, Beal MF (2008) Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer’s disease. Trends Mol Med 14:45–53

    CAS  PubMed  Google Scholar 

  129. Figueroa DJ et al (2002) Presenilin-dependent gamma-secretase activity modulates neurite outgrowth. Neurobiol Dis 9:49–60

    CAS  PubMed  Google Scholar 

  130. Hirata K et al (2005) A novel neurotrophic agent, T-817MA [1-{3-[2-(1-benzothiophen-5-yl) ethoxy] propyl}-3-azetidinol maleate], attenuates amyloid-beta-induced neurotoxicity and promotes neurite outgrowth in rat cultured central nervous system neurons. J Pharmacol Exp Therap 314:252–259

    CAS  Google Scholar 

  131. Hu M et al (2007) High content screen microscopy analysis of Ap(1-42)-induced neurite outgrowth reduction in rat primary cortical neurons: neuroprotective effects of alpha 7 neuronal nicotinic acetylcholine receptor ligands. Brain Res 1151:227–235

    CAS  PubMed  Google Scholar 

  132. Evans NA et al (2008) A beta(1-42) reduces synapse number and inhibits neurite outgrowth in primary cortical and hippocampal neurons: a quantitative analysis. J Neurosci Meth 175:96–103

    CAS  Google Scholar 

  133. Franke C et al (2007) Bcl-2 upregulation and neuroprotection in guinea pig brain following chronic simvastatin treatment. Neurobiol Dis 25:438–445

    CAS  PubMed  Google Scholar 

  134. Johnson-Anuna LN et al (2007) Simvastatin protects neurons from cytotoxicity by up-regulating Bcl-2 mRNA and protein. J Neurochem 101:77–86

    CAS  PubMed  Google Scholar 

  135. Cole GM et al (2009) Omega-3 fatty acids and dementia. Prostaglandins Leukot Essent Fatty Acids 81:213–221

    CAS  PubMed  Google Scholar 

  136. Ma QL et al (2009) Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. J Neurosci 29:9078–9089

    CAS  PubMed  Google Scholar 

  137. Eckert GP et al (2010) Plant derived omega-3-fatty acids protect mitochondrial function in the brain. Pharmacol Res 61(3):234–241

    CAS  PubMed  Google Scholar 

  138. Bordet T et al (2007) Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis. J Pharmacol Exp Therap 322:709–720

    CAS  Google Scholar 

  139. Schaffer S et al (2007) Hydroxytyrosol-rich olive mill wastewater extract protects brain cells in vitro and ex vivo. J Agric Food Chem 55:5043–5049

    CAS  PubMed  Google Scholar 

  140. Johnson-Anuna LN et al (2005) Chronic administration of statins alters multiple gene expression patterns in mouse cerebral cortex. J Pharmacol Exp Therap 312:786–793

    CAS  Google Scholar 

  141. Stoll S et al (1996) Ginkgo biloba extract (EGb 761) independently improves changes in passive avoidance learning and brain membrane fluidity in the aging mouse. Pharmacopsychiatry 29:144–149

    CAS  PubMed  Google Scholar 

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Correspondence to Walter E. Müller.

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Müller, W.E., Eckert, A., Kurz, C. et al. Mitochondrial Dysfunction: Common Final Pathway in Brain Aging and Alzheimer’s Disease—Therapeutic Aspects. Mol Neurobiol 41, 159–171 (2010). https://doi.org/10.1007/s12035-010-8141-5

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  • DOI: https://doi.org/10.1007/s12035-010-8141-5

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