Advertisement

Journal of Neural Transmission

, Volume 123, Issue 2, pp 107–111 | Cite as

Cerebrovascular and mitochondrial abnormalities in Alzheimer’s disease: a brief overview

  • Cristina Carvalho
  • Sónia C. Correia
  • George PerryEmail author
  • Rudy J. Castellani
  • Paula I. MoreiraEmail author
Neurology and Preclinical Neurological Studies - Review Article

Abstract

Multiple lines of evidence suggest that vascular alterations contribute to Alzheimer’s disease (AD) pathogenesis. It is also well established that mitochondrial abnormalities occur early in course of AD. Here, we give an overview of the vascular and mitochondrial abnormalities occurring in AD, including mitochondrial alterations in vascular endothelial cells within the brain, which is emerging as a common feature that bridges cerebral vasculature and mitochondrial metabolism.

Keywords

Alzheimer’s disease Brain vasculature Mitochondria Oxidative stress 

Notes

Acknowledgements

The authors’ work is supported by Quadro de Referência Estratégico Nacional (QREN DO-IT) and Alzheimer’s Association (NIRG-13-282387), by the Semmes Foundation, and by a grant from the National Institute on Minority Health and Health Disparities (G12MD007591) from the National Institutes of Health.

References

  1. Bosetti F, Brizzi F, Barogi S, Mancuso M, Siciliano G, Tendi EA et al (2002) Cytochrome c oxidase and mitochondrial F1F0-ATPase (ATP synthase) activities in platelets and brain from patients with Alzheimer’s disease. Neurobiol Aging 23:371–376CrossRefPubMedGoogle Scholar
  2. Bubber P, Haroutunian V, Fisch G, Blass JP, Gibson GE (2005) Mitochondrial abnormalities in Alzheimer brain: mechanistic implications. Ann Neurol 57:695–703CrossRefPubMedGoogle Scholar
  3. Carrano A, Hoozemans JJ, van der Vies SM, van Horssen J, de Vries HE, Rozemuller AJ (2012) Neuroinflammation and blood-brain barrier changes in capillary amyloid angiopathy. Neurodegener Dis 10:329–331CrossRefPubMedGoogle Scholar
  4. Carvalho C, Correia SC, Santos RX, Cardoso S, Moreira PI, Clark TA et al (2009) Role of mitochondrial-mediated signaling pathways in Alzheimer disease and hypoxia. J Bioenerg Biomembr 41:433–440PubMedCentralCrossRefPubMedGoogle Scholar
  5. Carvalho C, Santos MS, Baldeiras I, Oliveira CR, Seiça R, Moreira PI (2010) Chronic hypoxia potentiates age-related oxidative imbalance in brain vessels and synaptosomes. Curr Neurovasc Res 7:288–300CrossRefPubMedGoogle Scholar
  6. Castellani RJ, Smith MA, Perry G, Friedland RP (2004) Cerebral amyloid angiopathy: major contributor or decorative response to Alzheimer’s disease pathogenesis. Neurobiol Dis 25:599–602Google Scholar
  7. Chang HC, Chen TG, Tai YT, Chen TL, Chiu WT, Chen RM (2011) Resveratrol attenuates oxidized LDL-evoked Lox-1 signaling and consequently protects against apoptotic insults to cerebrovascular endothelial cells. J Cereb Blood Flow Metab 3:842–854CrossRefGoogle Scholar
  8. Chen Q, Vazquez EJ, Moghaddas S, Hoppel CL, Lesnefsky EJ (2003) Production of reactive oxygen species by mitochondria: central role of complex III. J Biol Chem 278:36027–36031CrossRefPubMedGoogle Scholar
  9. Cho DH, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z et al (2009) S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science 324:102–105PubMedCentralCrossRefPubMedGoogle Scholar
  10. Chou JL, Shenoy DV, Thomas N, Choudhary PK, Laferla FM, Goodman SR et al (2011) Early dysregulation of the mitochondrial proteome in a mouse model of Alzheimer’s disease. J Proteomics 74:466–479CrossRefPubMedGoogle Scholar
  11. Claudio L (1996) Ultrastructural features of the blood–brain barrier in biopsy tissue from Alzheimer’s disease patients. Acta Neuropathol 91:6–14CrossRefPubMedGoogle Scholar
  12. Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S et al (2014) Alzheimer’s Disease Cooperative Study Steering Committee; Solanezumab Study Group. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 370:311–321CrossRefPubMedGoogle Scholar
  13. Du H, Guo L, Fang F, Chen D, Sosunov AA, McKhann GM et al (2008) Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nat Med 14:1097–1105PubMedCentralCrossRefPubMedGoogle Scholar
  14. Guglielmotto M, Aragno M, Autelli R, Giliberto L, Novo E, Colombatto S et al (2009) The up-regulation of BACE1 mediated by hypoxia and ischemic injury: role of oxidative stress and HIF1alpha. J Neurochem 108:1045–1056CrossRefPubMedGoogle Scholar
  15. Hamdheydari L, Christov A, Ottman T, Hensley K, Grammas P (2003) Oxidized LDLs affect nitric oxide and radical generation in brain endothelial cells. Biochem Biophys Res Comm 311:486–490CrossRefPubMedGoogle Scholar
  16. Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS et al (2001) Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci 21:3017–3023PubMedGoogle Scholar
  17. Huang HM, Ou HC, Xu H, Chen HL, Fowler C, Gibson GE (2003) Inhibition of alpha ketoglutarate dehydrogenase complex promotes cytochrome c release from mitochondria, caspase-3 activation, and necrotic cell death. J Neurosci Res 74:309–317CrossRefPubMedGoogle Scholar
  18. Humpel C (2011) Chronic mild cerebrovascular dysfunction as a cause for Alzheimer’s disease? Exp Gerontol 46:225–232PubMedCentralCrossRefPubMedGoogle Scholar
  19. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA et al (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med 4:147CrossRefGoogle Scholar
  20. Iliff JJ, Chen MJ, Plog BA, Zeppenfeld DM, Soltero M, Yang L et al (2014) Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J Neurosci 34:16180–16193PubMedCentralCrossRefPubMedGoogle Scholar
  21. Johnson NA, Jahng GH, Weiner MW, Miller BL, Chui HC, Jagust WJ et al (2005) Pattern of cerebral hypoperfusion in Alzheimer disease and mild cognitive impairment measured with arterial spin-labeling MR imaging: initial experience. Radiology 234:851–859PubMedCentralCrossRefPubMedGoogle Scholar
  22. Khandelwal PJ, Herman AM, Hoe HS, Rebeck GW, Moussa CE (2011) Parkin mediates beclin-dependent autophagic clearance of defective mitochondria and ubiquitinated Abeta in AD models. Hum Mol Genet 20:2091–2102PubMedCentralCrossRefPubMedGoogle Scholar
  23. Kish SJ, Bergeron C, Rajput A, Dozic S, Mastrogiacomo F, Chang LJ et al (1992) Brain cytochrome oxidase in Alzheimer’s disease. J Neurochem 59:776–779CrossRefPubMedGoogle Scholar
  24. Kolev K, Skopál J, Simon L, Csonka E, Machovich R, Nagy Z (2003) Matrix metalloproteinase-9 expression in post-hypoxic human brain capillary endothelial cells: H2O2 as a trigger and NF-kappaB as a signal transducer. Thromb Haemost 90:528–537PubMedGoogle Scholar
  25. Kress BT, Iliff JJ, Xia M, Wang M, Wei HS, Zeppenfeld D et al (2014) Impairment of paravascular clearance pathways in the aging brain. Ann Neurol 76:845–861PubMedCentralCrossRefPubMedGoogle Scholar
  26. Kushnareva Y, Murphy AN, Andreyev A (2002) Complex I-mediated reactive oxygen species generation: modulation by cytochrome c and NAD(P)+ oxidation–reduction state. Biochem J 368:545–553PubMedCentralCrossRefPubMedGoogle Scholar
  27. Leuner K, Schütt T, Kurz C, Eckert SH, Schiller C, Occhipinti A et al (2012) Mitochondria-derived ROS lead to enhanced amyloid beta formation. Antioxid Redox Signal 16:1421–1433PubMedCentralCrossRefPubMedGoogle Scholar
  28. Moreira PI (2012) Alzheimer’s disease and diabetes: an integrative view of the role of mitochondria, oxidative stress and insulin. J Alzheimers Dis 30:S199–S215PubMedGoogle Scholar
  29. Moreira PI, Santos MS, Moreno A, Oliveira C (2001) Amyloid beta-peptide promotes permeability transition pore in brain mitochondria. Biosci Rep 21:789–800CrossRefPubMedGoogle Scholar
  30. Moreira PI, Santos MS, Moreno A, Rego AC, Oliveira C (2002) Effect of amyloid beta-peptide on permeability transition pore: a comparative study. J Neurosci Res 69:257–267CrossRefPubMedGoogle Scholar
  31. Moreira PI, Santos MS, Sena C, Nunes E, Seiça R, Oliveira CR (2005a) CoQ10 therapy attenuates amyloid beta-peptide toxicity in brain mitochondria isolated from aged diabetic rats. Exp Neurol 196:112–119CrossRefPubMedGoogle Scholar
  32. Moreira PI, Santos MS, Sena C, Seiça R, Oliveira CR (2005b) Insulin protects against amyloid beta-peptide toxicity in brain mitochondria of diabetic rats. Neurobiol Dis 18:628–637CrossRefPubMedGoogle Scholar
  33. Moreira PI, Santos MS, Oliveira CR (2007a) Alzheimer’s disease: a lesson from mitochondrial dysfunction. Antioxid Redox Signal 9:1621–1630CrossRefPubMedGoogle Scholar
  34. Moreira PI, Siedlak SL, Wang X, Santos MS, Oliveira CR, Tabaton M et al (2007b) Autophagocytosis of mitochondria is prominent in Alzheimer disease. J Neuropathol Exp Neurol 66:525–532CrossRefPubMedGoogle Scholar
  35. Murray IV, Proza JF, Sohrabji F, Lawler JM (2011) Vascular and metabolic dysfunction in Alzheimer’s disease: a review. Exp Biol Med (Maywood) 236:772–782CrossRefGoogle Scholar
  36. Nag S (2002) The blood-brain barrier and cerebral angiogenesis: lessons from the cold-injury model. Trends Mol Med 8:38–44CrossRefPubMedGoogle Scholar
  37. Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK et al (2001) Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 60:759–767CrossRefPubMedGoogle Scholar
  38. Panza F et al (2014) Efficacy and safety studies of gantenerumab in patients with Alzheimer’s disease. Expert Rev Neurother 14:973–986CrossRefPubMedGoogle Scholar
  39. Parker WD Jr, Mahr NJ, Filley CM, Parks JK, Hughes D, Young DA et al (1994) et al. Reduced platelet cytochrome c oxidase activity in Alzheimer’s disease. Neurology 44:1086–1090CrossRefPubMedGoogle Scholar
  40. Pu PB, Lu J, Moochhala S (2009) Involvement of ROS in BBB dysfunction. Free Radic Res 43:348–364CrossRefGoogle Scholar
  41. Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362:329–344CrossRefPubMedGoogle Scholar
  42. Resende R, Moreira PI, Proença T, Deshpande A, Busciglio J, Pereira C et al (2008) Brain oxidative stress in a triple-transgenic mouse model of Alzheimer disease. Free Radic Biol Med 44:2051–2057CrossRefPubMedGoogle Scholar
  43. Rombouts SA, Goekoop R, Stam CJ, Barkhof F, Scheltens P (2005) Delayed rather than decreased BOLD response as a marker for early Alzheimer’s disease. Neuroimage 26:1078–1085CrossRefPubMedGoogle Scholar
  44. Roy S, Rauk A (2005) Alzheimer’s disease and the ‘ABSENT’ hypothesis: mechanism for amyloid beta endothelial and neuronal toxicity. Med Hypotheses 65:123–137CrossRefPubMedGoogle Scholar
  45. Sabayan B, Jansen S, Oleksik AM, van Osch MJ, van Buchem MA, van Vliet P et al (2012) Cerebrovascular hemodynamics in Alzheimer’s disease and vascular dementia: a meta-analysis of transcranial Doppler studies. Ageing Res Rev 11:271–277CrossRefPubMedGoogle Scholar
  46. Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M et al (2014) Bapineuzumab 301 and 302 Clinical Trial Investigators. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 370:322–333PubMedCentralCrossRefPubMedGoogle Scholar
  47. Sun X, He G, Qing H, Zhou W, Dobie F, Cai F et al (2006) Hypoxia facilitates Alzheimer’s disease pathogenesis by up-regulating BACE1 gene expression. Proc Natl Acad Sci USA 103:18727–18732PubMedCentralCrossRefPubMedGoogle Scholar
  48. Valla J, Schneider L, Niedzielko T, Coon KD, Caselli R, Sabbagh MN et al (2006) Impaired platelet mitochondrial activity in Alzheimer’s disease and mild cognitive impairment. Mitochondrion 6:323–330PubMedCentralCrossRefPubMedGoogle Scholar
  49. Wang X, Su B, Fujioka H, Zhu X (2008a) Dynamin-like protein 1 reduction underlies mitochondrial morphology and distribution abnormalities in fibroblasts from sporadic Alzheimer’s disease patients. Am J Pathol 173:470–482PubMedCentralCrossRefPubMedGoogle Scholar
  50. Wang X, Su B, Siedlak SL, Moreira PI, Fujioka H, Wang Y et al (2008b) Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci USA 105:19318–19323PubMedCentralCrossRefPubMedGoogle Scholar
  51. Xu J, Chen S, Ku G, Ahmed SH, Xu J, Chen H et al (2001) Amyloid beta peptide-induced cerebral endothelial cell death involves mitochondrial dysfunction and caspase activation. J Cereb Blood Flow Metab 21:702–710CrossRefPubMedGoogle Scholar
  52. Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT, Brinton RD (2009) Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in female mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 106:14670–14675PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2015

Authors and Affiliations

  • Cristina Carvalho
    • 1
  • Sónia C. Correia
    • 1
    • 2
  • George Perry
    • 4
    • 5
    Email author
  • Rudy J. Castellani
    • 6
  • Paula I. Moreira
    • 1
    • 3
    Email author
  1. 1.CNC-Center for Neuroscience and Cell BiologyUniversity of CoimbraCoimbraPortugal
  2. 2.Institute for Interdisciplinary Research (IIIUC)University of CoimbraCoimbraPortugal
  3. 3.Faculty of Medicine, Institute of PhysiologyUniversity of CoimbraCoimbraPortugal
  4. 4.College of SciencesThe University of Texas at San AntonioSan AntonioUSA
  5. 5.Department of PathologyCase Western Reserve UniversityClevelandUSA
  6. 6.Division of NeuropathologyUniversity of MarylandBaltimoreUSA

Personalised recommendations