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Role of vascular hypoperfusion-induced oxidative stress and mitochondria failure in the pathogenesis of Alzheimer disease

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Abstract

Chronic vascular hypoperfusion induces oxidative stress and brain energy failure, and leads to neuronal death, which manifests as cognitive impairment and the development of brain pathology as in Alzheimer disease (AD). It is becoming more widely accepted that AD is characterized by impairments in energy metabolism. We hypothesize that hypoperfusion-induced mitochondrial failure plays a central role in the generation of reactive oxygen species, resulting in oxidative damage to brain cellular compartments, especially in the vascular endothelium and neuronal cell bodies in AD. All of these changes have been found to occur before pathology and coexist during the progression of AD. In this review we have summarized recent evidence and our own knowledge regarding the relationship between the hypoperfusion-induced vascular damage that initiates oxidative stress and mitochondrial abnormalities that appear to be a key target for the development of AD pathology. Future investigations into both the mechanisms behind amyloid β (Aß) deposition and the possible accelerating effects of environmental factors, such as chronic hypoxia/reperfusion, may open the door for effective pharmacological treatments of AD. We hypothesize that an imbalance between endothelium-derived vasoconstrictors and vasodilators, along with an antioxidant system deficiency and mitochondria lesions are prominent in AD. Future studies examining the importance of mitochondrial pathophysiology in different brain cellular compartments may provide insight not only into neurodegenerative and/or cerebrovascular disease pathobiology but may also provide targets for treating these conditions.

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References

  • Acuna-Castroviejo D, M Martin, M Macias, G Escames, J Leon, H Khaldy and RJ Reiter (2001) Melatonin, mitochondria, and cellular bioenergetics.J. Pineal Res. 30, 65–74.

    Article  PubMed  CAS  Google Scholar 

  • Al Abdulla NA and LJ Martin (1998) Apoptosis of retrogradely degenerating neurons occurs in association with the accumulation of perikaryal mitochondria and oxidative damage to the nucleus.Am. J. Pathol. 153, 447–456.

    Google Scholar 

  • Aliev G (2002) Is non-genetic Alzheimer's disease a vascular disorder with neurodegenerative consequences?.J. Alzheimer's Disease 4, 513–516.

    Google Scholar 

  • Aliev G and G Burnstock (1998) Watanabe rabbits with heritable hypercholesterolaemia: a model of atherosclerosis.Histol. Histopathol. 13, 797–817.

    PubMed  CAS  Google Scholar 

  • Aliev G, R Cirillo, E Salvatico, M Paro and M Prosdocimi (1993) Changes in vessel ultrastructure during ischemia and reperfusion of rabbit hindlimb: implications for therapeutic intervention.Microvasc. Res. 46, 65–76.

    Article  PubMed  CAS  Google Scholar 

  • Aliev G, P Bodin and G Burnstock (1998) Free radical generators cause changes in endothelial and inducible nitric oxide synthases and endothelin-1 immunoreactivity in endothelial cells from hyperlipidemic rabbits.Mol. Genet. Metab. 63, 191–197.

    Article  PubMed  CAS  Google Scholar 

  • Aliev G, MA Smith, H Vinters, AB Johnson, A Nunomura and G Perry (1999) Mitochondria abnormalities mark vulnerable neurons in Alzheimer's disease.J. Neuropathol. Exp. Neurol. 58, 511.

    Article  Google Scholar 

  • Aliev G, J Shi, JC Lamanna, BT Lamb and RP Friedland (2000a) Atherosclerotic-like changes of the wall of cerebral microvessels in transgenic mice overexpressing amyloid β.Neurobiol Aging 21, 1S, S267, p. 1224.

    Google Scholar 

  • Aliev G, J Shi, G Perry, BT Lamb, JC Lamanna and RP Friedland (2000b) Neuronal mitochondrial abnormalities in yeast artificial chromosome (YAC) transgenic mice overexpressing amyloid precursor protein (APP).Soc. Neurosci. Abstr. 30, 26: 301.4.

    Google Scholar 

  • Aliev G, J Shi, G Perry, RP Friedland and JC Lamanna (2000c) Decreased constitutive nitric oxide synthase, but increased inducible nitric oxide synthase and endothelin-1 immunoreactivity in aortic endothelial cells of donryu rats on a cholesterol-enriched diet.Anat. Rec. 260, 16–25.

    Article  PubMed  CAS  Google Scholar 

  • Aliev G, G Perry, BT Lamb, D Seyidova, ML Neal, SL Siedlak, JC LaManna, MA Smith and RP Friedland (2001a) Aged YAC AbPP transgenic mice develop atherosclerotic lesions and mitochondria DNA deletions in brain microvessels without exogenous cholesterol supplementation.Soc. Neurosci. Abstr. 752.12 (Abstr.)

  • Aliev G, MA Smith, M Turmaine, ML Neal, TV Zimina, RP Friedland, G Perry, JC Lamanna and G Burnstock (2001b) Atherosclerotic lesions are associated with increased immunoreactivity for inducible nitric oxide synthase and endothelin-1 in thoracic aortic intimal cells of hyperlipidemic Watanabe rabbits.Exp. Mol. Pathol. 71, 40–54.

    Article  PubMed  CAS  Google Scholar 

  • Aliev G, G Perry, D Seyidova, BT Lamb, ML Neal, SL Siedlak, MA Smith, JC LaManna and RP Friedland (2002a) The role of mitochondria failure in the development of AD-like pathology in an aged transgenic mouse model of AD.Neurobiol. Aging 23, S414-P.P.-1525.

    Google Scholar 

  • Aliev G, D Seyidova, BT Lamb, ML Neal, SL Siedlak, H Vinters, JC LaManna, RP Friedland, E Head, G Perry and CW Cotman (2002b) Atherosclerotic lesions and mitochondria DNA deletions in brain microvessels as a central target for the development of human AD and AD-like pathology in a aged YAC AßPP transgenic mice.Ann. NY Acad. Sci. 977, 45–64.

    PubMed  CAS  Google Scholar 

  • Aliev G, MA Smith, D Seyidova, ML Neal, BT Lamb, A Nunomura, EK Gasimov, HV Vinters, G Perry, JC Lamanna and RP Friedland (2002c) The role of oxidative stress in the pathophysiology of cerebrovascular lesions in Alzheimer's disease.Brain Pathol. 12, 21–35.

    PubMed  CAS  Google Scholar 

  • Aliev G, MA Smith, D Seyidova, ML Neal, J Shi, M Loizidou, M Turmaine, RP Friedland, I Taylor, G Burnstock, G Perry and JC Lamanna (2002d) Increased expression of NOS and ET-1 immunoreactivity in human colorectal metastatic liver tumours is associated with selective depression of constitutive NOS immunoreactivity in vessel endothelium.J. Submicrosy. Cytol. Pathol. 34, 37–50.

    CAS  Google Scholar 

  • Aliev G, D Seyidova, BT Lamb, ME Obrenovich, SL Siedlak, H Vinters, JC LaManna, MA Smith and G Perry (2003a) Mitochondria and vascular lesions as a central target for the development of Alzheimer's disease and Alzheimer disease-like pathology in transgenic mice.Neurological Res. 25, 665–674.

    Article  Google Scholar 

  • Aliev G, D Seyidova, AK Raina, ME Obrenovich, ML Neal, SL Siedlak, BT Lamb, H Vinters, JC LaManna, MA Smith and G Perry (2003b) Vascular hypoperfusion, mitochondria failure and oxidative stress in Alzheimer disease.Proc. Indian Natl. Science Academy B69, 209–238.

    Google Scholar 

  • Baggio G, S Donazzan, D Monti, D Mari, S Martini, C Gabelli, VM Dalla, L Previato, M Guido, S Pigozzo, I Cortella, G Crepaldi and C Franceschi (1998) Lipoprotein(a) and lipoprotein profile in healthy centenarians: a reappraisal of vascular risk factors.FASEB J. 12, 433–437.

    PubMed  CAS  Google Scholar 

  • Beal MF (1995) Aging, energy, and oxidative stress in neurodegenerative diseases.Ann. Neurol. 38, 357–366.

    Article  PubMed  CAS  Google Scholar 

  • Beckman KB and BN Ames (1998a) Mitochondrial aging: open questions.Ann. NY Acad. Sci. 854, 118–127.

    Article  PubMed  CAS  Google Scholar 

  • Beckman KB and BN Ames (1998b) The free radical theory of aging matures.Physiol. Rev. 78, 547–581.

    PubMed  CAS  Google Scholar 

  • Beckman KB and BN Ames (1999) Endogenous oxidative damage of mtDNA.Mutat. Res. 424, 51–58.

    PubMed  CAS  Google Scholar 

  • Bonilla E, K Tanji, M Hirano, TH Vu, S DiMauro and EA Schon (1999) Mitochondrial involvement in Alzheimer's disease.Biochim. Biophys. Acta 1410, 171–182.

    Article  PubMed  CAS  Google Scholar 

  • Cash AD, G Aliev, SL Siedlak, H Fujioka, HV Vinters, M Tabaton, AB Johnson, M Paula-Barbosa, J Avila, PK Jones, MA Smith and G Perry (2003) Microtubule reduction in Alzheimer disease and aging is independent of TAU filament formation.Am. J. Pathol. 162, 1623–1627.

    PubMed  CAS  Google Scholar 

  • Castellani R, K Hirai, G Aliev, KL Drew, A Nunomura, A Takeda, AD Cash, ME Obrenovich, G Perry and MA Smith (2002) Role of mitochondrial dysfunction in Alzheimer's disease.J. Neurosci. Res. 70, 357–360.

    Article  PubMed  CAS  Google Scholar 

  • Chen G, KS Chen, J Knox, J Inglis, A Bernard, SJ Martin, A Justice L McConlogue, D Games, SB Freedman and RG Morris (2000) A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer's disease.Nature 408, 975–979.

    Article  PubMed  CAS  Google Scholar 

  • Cirillo R, E Salvatico, G Aliev and M Prosdocimi (1992) Effect of cloricromene during ischemia and reperfusion of rabbit hindlimb: evidence for an involvement of leukocytes in reperfusion-mediated tissue and vascular injury.J. Cardiovasc. Pharmacol. 20, 969–975.

    Article  PubMed  CAS  Google Scholar 

  • Cirillo R, G Aliev, EJ Hornby and M Prosdocimi (1994) Endothelium as a therapeutical target in peripheral occlusive arterial diseases: consideration for pharmacological interventions.Pharmacol. Res. 29, 293–311.

    Article  PubMed  CAS  Google Scholar 

  • Coria F, E Castano, F Prelli, M Larrondo-Lillo, S van Duinen, ML Shelanski and B Frangione (1988) Isolation and characterization of amyloid P component from Alzheimer's disease and other types of cerebral amyloidosis.Lab. Invest. 58, 454–458.

    PubMed  CAS  Google Scholar 

  • Cormier A, C Morin, R Zini, J Tillement and G Lagrue (2001)In vitro effects of nicotine on mitochondrial respiration and superoxide anion generation.Brain Res. 900, 72–79.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • De Jong GI, RA De Vos, EN Steur and PG Luiten (1997) Cerebrovascular hypoperfusion: a risk factor for Alzheimer's disease? Animal model and postmortem human studies.Ann. NY Acad. Sci. 826, 56–74.

    Article  PubMed  Google Scholar 

  • de la Torre JC (1997) Hemodynamic consequences of deformed microvessels in the brain in Alzheimer's disease.Ann. NY Acad. Sci. 826, 75–91.

    Article  PubMed  Google Scholar 

  • de la Torre JC (2000) Critically attained threshold of cerebral hypoperfusion: the CATCH hypothesis of Alzheimer's pathogenesis.Neurobiol. Aging 21, 331–342.

    Article  PubMed  Google Scholar 

  • de la Torre JC (2002a) Alzheimer's disease: how does it start?.J. Alzheimer's Disease 4, 497–512.

    Google Scholar 

  • de la Torre JC (2002b) Alzheimer disease as a vascular disorder: nosological evidence.Stroke 33, 1152–1162.

    Article  PubMed  Google Scholar 

  • de la Torre JC (2002c) Vascular basis of Alzheimer's pathogenesis.Ann. NY Acad. Sci. 977, 196–215.

    Article  PubMed  Google Scholar 

  • de la Torre JC and GB Stefano (2000) Evidence that Alzheimer's disease is a microvascular disorder: the role of constitutive nitric oxide.Brain Res. Brain Res. Rev. 34, 119–136.

    Article  PubMed  Google Scholar 

  • Duff K (1998) Transgenic models for Alzheimer's disease.Neuropathol. Appl. Neurobiol. 24, 101–103.

    Article  PubMed  CAS  Google Scholar 

  • Etiene D, J Kraft, N Ganju, T Gomez-Isla, B Gemelli, BT Hyman, T Hedley-Whyte, JR Wands and SM de la Monte (1998) Cerebrovascular pathology contributes to the heterogeneity of Alzheimer's disease.J. Alzheimer's Disease 1, 119–134.

    Google Scholar 

  • Fiskum G, AN Murphy and MF Beal (1999) Mitochondria in neurodegeneration: acute ischemia and chronic neurodegenerative diseases.J. Cereb. Blood Flow Metab. 19, 351–369.

    Article  PubMed  CAS  Google Scholar 

  • Friston KJ and RS Frackowiak (1991) Cerebral function in aging and Alzheimer's disease: the role of PET.Electroencephalogr. Clin. Neurophysiol. Suppl. 42, 355–365.

    PubMed  CAS  Google Scholar 

  • Granger DN, JN Benoit, M Suzuki and MB Grisham (1989) Leukocyte adherence to venular endothelium during ischemia-reperfusion.Am. J. Physiol. 257, G683-G688.

    PubMed  CAS  Google Scholar 

  • Grant DN (1997) Dietary links to Alzheimer's disease.Alzheimer's Disease Rev. 2, 42–55.

    CAS  Google Scholar 

  • Hirai K, G Aliev, A Nunomura, H Fujioka, RL Russell, CS Atwood, AB Johnson, Y Kress, HV Vinters, M Tabaton, S Shimohama, AD Cash, SL Siedlak, PL Harris, PK Jones, RB Petersen, G Perry and MA Smith (2001) Mitochondrial abnormalities in Alzheimer's disease.J. Neurosci. 21, 3017–3023.

    PubMed  CAS  Google Scholar 

  • Hock BJJ and BT Lamb (2001) Transgenic mouse models of Alzheimer's disease.Trends. Genet. 17, S7-S12.

    Article  PubMed  CAS  Google Scholar 

  • Jakobovits A, BT Lamb and KR Peterson (2000) Production of transgenic mice with yeast artificial chromosomes.Methods Mol. Biol. 136, 435–453.

    PubMed  CAS  Google Scholar 

  • Joachim CL, JH Morris and DJ Selkoe (1989) Diffuse senile plaques occur commonly in the cerebellum in Alzheimer's disease.Am. J. Pathol. 135, 309–319.

    PubMed  CAS  Google Scholar 

  • Kalaria RN (1999) The blood-brain barrier and cerebrovascular pathology in Alzheimer's disease.Ann. NY Acad. Sci. 893, 113–125.

    Article  PubMed  CAS  Google Scholar 

  • Kalaria RN (2000) The role of cerebral ischemia in Alzheimer's disease.Neurobiol. Aging 21, 321–330.

    Article  PubMed  CAS  Google Scholar 

  • Kalaria RN and C Ballard (1999) Overlap between pathology of Alzheimer disease and vascular dementia.Alzheimer Dis. Assoc. Disord. 13 Suppl. 3, S115-S123.

    Article  PubMed  Google Scholar 

  • Kawai M, RN Kalaria, SI Harik and G Perry (1990) The relationship of amyloid plaques to cerebral capillaries in Alzheimer's disease.Am. J. Pathol. 137, 1435–1446.

    PubMed  CAS  Google Scholar 

  • Knebl J, P DeFazio, MB Clearfield, L Little, WJ McConathy, R McPherson and AG Lacko (1994) Plasma lipids and cholesterol esterification in Alzheimer's disease.Mech. Ageing Dev. 73, 69–77.

    Article  PubMed  CAS  Google Scholar 

  • Koudinov AR, TT Berezov and NV Koudinova (1998) Alzheimer's amyloid beta and lipid metabolism: a missing link?.FASEB J. 12, 1097–1099.

    PubMed  CAS  Google Scholar 

  • Kulnane LS and BT Lamb (2001) Neuropathological characterization of mutant amyloid precursor protein yeast artificial chromosome transgenic mice.Neurobiol. Dis. 8, 982–992.

    Article  PubMed  CAS  Google Scholar 

  • Kulnane LS, EJ Lehman, BJ Hock, KD Tsuchiya and BT Lamb (2002) Rapid and efficient detection of transgene homozygosity by FISH of mouse fibroblasts.Mamm. Genome 13, 223–226.

    Article  PubMed  CAS  Google Scholar 

  • Kumar A, MB Schapiro, JV Haxby, CL Grady and RP Friedland (1990) Cerebral metabolic and cognitive studies in dementia with frontal lobe behavioral features.J. Psychiatr. Res. 24, 97–109.

    Article  PubMed  CAS  Google Scholar 

  • Kuo, YM, MR Emmerling, CL Bisgaier, AD Essenburg, HC Lampert, D Drumm and AE Roher (1998) Elevated low-density lipoprotein in Alzheimer's disease correlates with brain abeta 1–42 levels.Biochem. Biophys. Res. Commun. 252, 711–715.

    Article  PubMed  CAS  Google Scholar 

  • Lamb BT, LM Call, HH Slunt, KA Bardel, AM Lawler, CB Eckman, SG Younkin, G Holtz, SL Wagner, DL Price, SS Sisodia and JD Gearhart (1997) Altered metabolism of familial Alzheimer's disease-linked amyloid precursor protein variants in yeast artificial chromosome transgenic mice.Hum. Mol. Genet. 6, 1535–1541.

    Article  PubMed  CAS  Google Scholar 

  • Lamb BT, KA Bardel, LS Kulnane, JJ Anderson, G Holtz, SL Wagner, SS Sisodia and EJ Hoeger (1999) Amyloid production and deposition in mutant amyloid precursor protein and presenilin-1 yeast artificial chromosome transgenic mice.Nat. Neurosci. 2, 695–697

    Article  PubMed  CAS  Google Scholar 

  • Lin B, MD Ginsberg and R Busto (2001) Hyperglycemic but not normoglycemic global ischemia induces marked early intraneuronal expression of beta-amyloid precursor protein.Brain Res. 888, 107–116.

    Article  PubMed  CAS  Google Scholar 

  • Lovell MA, C Xie and WR Markesbery (1998) Decreased glutathione transferase activity in brain and ventricular fluid in Alzheimer's disease.Neurology 51, 1562–1566.

    PubMed  CAS  Google Scholar 

  • Markesbery WR (1997) Oxidative stress hypothesis in Alzheimer's disease.Free Radic. Biol. Med. 23, 134–147.

    Article  PubMed  CAS  Google Scholar 

  • Markesbery WR and JM Carney (1999) Oxidative alterations in Alzheimer's disease.Brain Pathol. 9, 133–146.

    PubMed  CAS  Google Scholar 

  • Mecocci P, U MacGarvey, AE Kaufman, D Koontz, JM Shoffner, DC Wallace and MF Beal (1993) Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain.Ann. Neurol. 34, 609–616.

    Article  PubMed  CAS  Google Scholar 

  • Mecocci P, U MacGarvey and MF Beal (1994) Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease.Ann. Neurol. 36, 747–751.

    Article  PubMed  CAS  Google Scholar 

  • Mecocci P, MF Beal, R Cecchetti, MC Polidori, A Cherubini, F Chionne, L Avellini, G Romano and U Senin (1997) Mitochondrial membrane fluidity and oxidative damage to mitochondrial DNA in aged and AD human brain.Mol. Chem. Neuropathol. 31, 53–64.

    Article  PubMed  CAS  Google Scholar 

  • Meguro K, X Blaizot, Y Kondoh, C Le Mestric, JC Baron and C Chavoix (1999) Neocortical and hippocampal glucose hypometabolism following neurotoxic lesions of the entorhinal and perirhinal cortices in the non-human primate as shown by PET. Implications for Alzheimer's disease.Brain 122, 1519–1531.

    Article  PubMed  Google Scholar 

  • Montine TJ, KS Montine and LL Swift (1997) Central nervous system lipoproteins in Alzheimer's disease.Am. J. Pathol. 151, 1571–1575.

    PubMed  CAS  Google Scholar 

  • Neve RL and NK Robakis (1998) Alzheimer's disease: a re-examination of the amyloid hypothesis.Trends Neurosci. 21, 15–19.

    Article  PubMed  CAS  Google Scholar 

  • Nunomura A, G Perry, K Hirai, G Aliev, A Takeda, S Chiba and MA Smith (1999a) Neuronal RNA oxidation in Alzheimer's disease and Down's syndrome.Ann. NY Acad. Sci. 893, 362–364.

    Article  PubMed  CAS  Google Scholar 

  • Nunomura A, G Perry, MA Pappolla, R Wade, K Hirai, S Chiba and MA Smith (1999b) RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer's disease.J. Neurosci. 19, 1959–1964.

    PubMed  CAS  Google Scholar 

  • Nunomura A, G Perry, G Aliev, K Hirai, A Takeda, EK Balraj, PK Jones, H Ghanbari, T Wataya, S Shimohama, S Chiba, CS Atwood, RB Petersen and MA Smith (2001) Oxidative damage is the carliest event in Alzheimer disease.J. Neuropathol. Exp. Neurol. 60, 759–767.

    PubMed  CAS  Google Scholar 

  • Perry G, A Nunomura, K Hirai, A Takeda, G Aliev and MA Smith (2000) Oxidative damage in Alzheimer's disease: the metabolic dimension.Int. J. Dev. Neurosci. 18, 417–421.

    Article  PubMed  CAS  Google Scholar 

  • Prasad MR, MA Lovell, M Yatin, H Dhillon and WR Markesbery (1998) Regional membrane phospholipid alterations in Alzheimer's disease.Neurochem. Res. 23, 81–88.

    Article  PubMed  CAS  Google Scholar 

  • Puglielli L, RE Tanzi and DM Kovacs (2003) Alzheimer's disease: the cholesterol connection.Nat. Neurosci. 6, 345–351.

    Article  PubMed  CAS  Google Scholar 

  • Refolo LM, MA Pappolla, B Malester, J LaFrancois, T Bryant-Thomas, R Wang, GS Tint, K Sambamurti and K Duff (2000) Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model.Neurobiol. Dis. 7, 321–331.

    Article  PubMed  CAS  Google Scholar 

  • Sala A, GM Aliev, G Rossoni, F Berti, C Buccellati, G Burnstock, G Folco and J Maclouf (1996) Morphological and functional changes of coronary vasculature caused by transcellular biosynthesis of sulfidopeptide leukotrienes in isolated heart of rabbit.Blood 87, 1824–1832.

    PubMed  CAS  Google Scholar 

  • Salvatico E, GM Aliev, D Novello and M Prosdocimi (1994) Functional depression of isolated perfused rat heart mediated by activated leukocytes: protective effect of cloricromene.J. Cardiovasc. Pharmacol. 24, 638–647.

    Article  PubMed  CAS  Google Scholar 

  • Sayre LM, DA Zelasko, PL Harris, G Perry, RG Salomon and MA Smith (1997) 4-Hydroxynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer's disease.J. Neurochem. 68, 2092–2097.

    PubMed  CAS  Google Scholar 

  • Schulz JB, RT Matthews, T Klockgether, J Dichgans and MF Beal (1997) The role of mitochondrial dysfunction and neuronal nitric oxide in animal models of neurodegenerative diseases.Mol. Cell Biochem. 174, 193–197.

    Article  PubMed  CAS  Google Scholar 

  • Shankar A, M Loizidou, G Aliev, S Fredericks, D Holt, PB Boulos, G Burnstock and I Taylor (1998) Raised endothelin 1 levels in patients with colorectal liver metastases.Br. J. Surg. 85, 502–506.

    Article  PubMed  CAS  Google Scholar 

  • Shi J, G Perry, G Aliev, MA Smith, KH Ashe and RP Friedland (1999) Serum amyloid P is not present in amyloid beta deposits of a transgenic animal model.Neuroreport 10, 3229–3232.

    Article  PubMed  CAS  Google Scholar 

  • Shi J, G Perry, MS Berridge, G Aliev, SL Siedlak, MA Smith, JC Lamanna and RP Friedland (2002a) Labeling of cerebral amyloid beta depositsin vivo using intranasal basic fibroblast growth factor and serum amyloid P component in mice.J. Nucl. Med. 43, 1044–1051.

    PubMed  CAS  Google Scholar 

  • Shi J, D Seyidova, G Perry, ML Neal, SL Siedlak, MA Smith, JC LaManna, RP Friedland and G Aliev (2002b) Neuronal mitochondria abnormalities in a transgenic mouse model overex-pressing amyloid beta.Soc. Neurosci. Abstr. 295.20.

  • Smith MA, S Taneda, PL Richey, S Miyata, SD Yan, D Stern, LM Sayre, VM Monnier and G Perry (1994) Advanced Maillard reaction end products are associated with Alzheimer disease pathology.Proc. Natl. Acad. Sci. USA 91, 5710–5714.

    Article  PubMed  CAS  Google Scholar 

  • Smith MA, G Perry, PL Richey, LM Sayre, VE Anderson, MF Beal and N Kowall (1996a) Oxidative damage in Alzheimer's.Nature 382, 120–121.

    Article  PubMed  CAS  Google Scholar 

  • Smith MA, LM Sayre and G Perry (1996b) Is Alzheimer's disease of oxidative stress?Alzheimer's Disease Rev. 1, 63–67.

    CAS  Google Scholar 

  • Smith MA, GJ Petot and G Perry (1997a) Diet and oxidative stress: a novel synthesis of epidemiological data on Alzheimer's disease.Alzheimer's Disease Rev. 2, 58–60.

    CAS  Google Scholar 

  • Smith MA, PL Richey Harris, LM Sayre, JS Beckman and G Perry (1997b) Widespread peroxynitrite-mediated damage in Alzheimer's disease.J. Neurosci. 17, 2653–2657.

    PubMed  CAS  Google Scholar 

  • Smith MA, CA Rottkamp, A Nunomura, AK Raina and G Perry (2000) Oxidative stress in Alzheimer's disease.Biochim. Biophys. Acta 1502, 139–144.

    PubMed  CAS  Google Scholar 

  • Sparks DL (1997) Coronary artery disease, hypertension, ApoE, and cholesterol: a link to Alzheimer's disease?Ann. NY Acad. Sci. 826, 128–146.

    Article  PubMed  CAS  Google Scholar 

  • Sparks DL, YM Kuo, A Roher, T Martin and RJ Lukas (2000) Alterations of Alzheimer's disease in the cholesterol-fed rabbit. including vascular inflammation. Preliminary observations.Ann. NY Acad. Sci. 903, 335–344.

    Article  PubMed  CAS  Google Scholar 

  • Stewart PA, K Hayakawa, MA Akers and HV Vinters (1992) A morphometric study of the blood-brain barrier in Alzheimer's disease.Lab. Invest. 67, 734–742.

    PubMed  CAS  Google Scholar 

  • Tagliavini F, J Ghiso, WF Timmers, G Giaccone, O Bugiani and B Frangione (1990) Coexistence of Alzheimer's amyloid precursor protein and amyloid protein in cerebral vessel walls.Lab. Invest. 62, 761–767.

    PubMed  CAS  Google Scholar 

  • Wallace DC (1997) Mitochondrial DNA in aging and disease.Sci. Am. 277, 40–47.

    Article  PubMed  CAS  Google Scholar 

  • Wallace DC (1999) Mitochondrial diseases in man and mouse.Science 283, 1482–1488.

    Article  PubMed  CAS  Google Scholar 

  • Wong PC, H Cai, DR Borchelt and DL Price (2002) Genetically engenired mouse models of neurodegenerative diseases.Nat. Neurosci. 5, 633–639.

    Article  PubMed  CAS  Google Scholar 

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  1. The Microscopy Research Center, School of Medicine, Case Western Reserve University, 44106, Cleveland, OH, USA

    Gjumrakch Aliev & George Perry

  2. Department of Pathology, School of Medicine, Case Western Reserve University, 44106, Cleveland, OH, USA

    Gjumrakch Aliev, Mark A. Smith, Mark E. Obrenovich, Jack C. de la Torre & George Perry

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  1. Gjumrakch Aliev
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  2. Mark A. Smith
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Correspondence to Gjumrakch Aliev or George Perry.

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Aliev, G., Smith, M.A., Obrenovich, M.E. et al. Role of vascular hypoperfusion-induced oxidative stress and mitochondria failure in the pathogenesis of Alzheimer disease. neurotox res 5, 491–504 (2003). https://doi.org/10.1007/BF03033159

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