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Влияние нитрендипина на Ca2+-гомеостаз нейронов и активность цитотоксических факторов при болезни Альцгеймера
Влияние нитрендипина на Ca2+-гомеостаз нейронов и активность цитотоксических факторов при болезни Альцгеймера
Асташкин Е.И. Влияние нитрендипина на Ca2+-гомеостаз нейронов и активность цитотоксических факторов при болезни Альцгеймера. Consilium Medicum. 2017; 19 (10): 137–142. DOI: 10.26442/2075-1753_19.10.137-142
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Аннотация
В обзоре рассматриваются гипотеза «амилоидного каскада» и «кальциевая» гипотеза в возникновении и прогрессировании болезни Альцгеймера в свете последних экспериментальных данных. Особое внимание уделено изменению гомеостаза ионов Са2+- и Са2+-сигнализации при действии на нейроны цитотоксических β-амилоидных пептидов (Аβ-пептидов) и гиперфосфорилированных тау-белков. На примере дигидропиридинового блокатора Са2+-каналов нитрендипина приводятся новые механизмы его защитного действия, связанные со снижением образования Аβ-пептидов и их удаления из мозга в кровь (клиренсом Аβ).
Ключевые слова: болезнь Альцгеймера, амилоидный каскад, кальциевая гипотеза, нитрендипин, блокаторы кальциевых каналов, β-амилоидные пептиды.
Key words: Alzheimer's disease, amyloid cascade, calcium hypothesis, nitrendipine, calcium channel blockers, β-amyloid peptides.
Ключевые слова: болезнь Альцгеймера, амилоидный каскад, кальциевая гипотеза, нитрендипин, блокаторы кальциевых каналов, β-амилоидные пептиды.
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Key words: Alzheimer's disease, amyloid cascade, calcium hypothesis, nitrendipine, calcium channel blockers, β-amyloid peptides.
Полный текст
Список литературы
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16. Xu X. g-Secretase Catalyzes Sequential Cleavages of the AbPP Transmembrane Domain. J Cell 2006; 126 (5): 981–93.
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29. Mai A, Valente S, Meade S et al. Study of 1,4-dihydropyridine structural scaffold: discovery of novel sirtuin activators and inhibitors. J Med Chem 2009; 52: 5496–504.
30. Deane R, Yan ShD, Submamaryan RK et al. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med 2003; 9: 907–13.
31. Shibata M al. Clearance of Alzheimer’s amyloid-ss(1–40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest 2000; 106: 1489–99.
32. Gosselet F, Saint-Pol J, Candela P, Fenart L. Amyloid-peptides, Alzheimer's Disease and the Blood-Brain Barrier. Cur Alzheimer Res 2013; 10: 1–19.
33. Bachmeier C, Mullan M, Paris D. Characterization and use of human brain microvascular endothelial cells to examine beta-amyloid exchange in the blood-brain barrier. Cytotechnology 2010; 62: 519–29.
34. Bell RD, Zlokovic BV. Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer’s disease. Acta Neuropathol 2009; 118: 103–13.
35. Deane R, Bell RD, Sagare A, Zlokovic BV. Clearance of amyloid-beta peptide across the blood-brain barrier: implication for therapies in Alzheimer’s disease. CNS Neurol Disord Drug Targets 2009; 8: 16–30.
36. Zlokovic BV, Yamada S, Holtzman D et al. Clearance of amyloid beta-peptide from brain: transport or metabolism? Nat Med 2000; 6: 718–9.
2. Magi S, Castaldo P, Macri ML et al. Intracellular calcium disregulation: implications for Alzheimer’s Disease. Hindawi Publishing Corporation. BioMed Res Int Volume 2016; Article ID 6701324.
3. Forette F et al. Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet 1998; 352: 1347–51.
4. Fritze J, Walden J et al. Clinical findings with nimodipine in dementia: test of the calcium hypothesis. J Neural Transm Suppl 1995; 46: 439–53.
5. Tollefson GD. Short-term effects of the calcium channel blocker nimodipine (Bay-e-9736) in the management of primary degenerative dementia. Biol Psychiatry 1990; 27: 1133–42.
6. Anekonda ThS, Quinn JF, Harris Ch et al. L-type voltage-gated calcium channel blockade with isradipine as a therapeutic strategy for Alzheimer’s disease. Neurobiol Dis 2011; 41 (1): 62–70.
7. Woltjer RL. Role of glutathione in intracellular amyloid-alpha precursor protein/carboxy-terminal fragment aggregation and associated cytotoxicity. J Neurochem 2005; 93: 1047–56.
8. Woltjer RL et al. Effects of chemical chaperones on oxidative stress and detergent-insoluble species formation following conditional expression of amyloid precursor protein carboxy-terminal fragment. Neurobiol Dis 2007; 25: 427–37.
9. Wadsworth TL et al. Evaluation of coenzyme Q as an antioxidant strategy for Alzheimer's disease. J Alzheimers Dis 2008; 14: 225–34.
10. Demuro A, Parker I, Stutzmann G.E. Calcium signaling and amyloid toxicity in Alzheimer disease. J Biol Chem 2010; 285 (17): 12463–8.
11. Berridge MJ. Calcium hypothesis of Alzheimer’s disease. Pflugers Arch – Eur J Physiol. DOI: 10.1007/s00424-009-0736-1
12. Kawahara M, Negishi-Kato M, Sadakane Y. Calcium dyshomeostasis and neurotoxicity of Alzheimer's beta-amyloid protein. Expert Rev Neurother 2009; 9 (5): 681–93.
13. Zhang Y, Li P, Feng J, Wu M. Dysfunction of NMDA receptors in Alzheimer’s disease. Neurol Sci 2016; 37: 1039–47.
14. Toda T, Noda Y, Ito G et al. Presenilin-2 mutation causes early amyloid accumulation and memory impairment in a transgenic mouse model of Alzheimer’s disease. Hindawi Publishing Corporation J Biomed Biotechnol Volume 2011; Article ID 617974.
15. Tu H, Nelson O, Bezprozvanny A et al. Presenilins Form ER Ca2+ Leak Channels, a Function Disrupted by Familial Alzheimer's Disease-Linked Mutations. Alzheimers Dis 2009; 16 (2): 211–24.
16. Xu X. g-Secretase Catalyzes Sequential Cleavages of the AbPP Transmembrane Domain. J Cell 2006; 126 (5): 981–93.
17. Supnet Ch, Bezprozvanny I. The dysregulation of intracellular calcium in Alzheimer disease. Cell Calcium 2010; 47 (2): 183–9.
18. Nussbaum JM, Seward ME, Bloom GS. Alzheimer disease. A tale of two prions. Prion 2013; 7 (1): 14–9.
19. Shu-Ming Huang, Akihiro Mouri, Hideko Kokubo et al. Neprilysin-sensitive synapse-associated amyloid-b peptide oligomers impair neuronal plasticity and cognitive function. J Biol Chem 2006; 281 (26): 17941–51.
20. Eisele Y, Monteiro C, Fearns C et al. Targeting Protein Aggregation for the Treatment of Degenerative Diseases. Nat Rev Drug Discov 2015; 14 (11): 759–80.
21. Forette F et al. The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study. Arch Intern Med 2002; 162: 2046–52.
22. Hanon O, Forette F. Prevention of dementia: lessons from SYST-EUR and PROGRESS. J Neurol Sci 2004; 226: 71–4.
23. Paris D, Bachmeier C, Patel N. Selective antihypertensive dihydropyridines lower Ab accumulation by targeting both the production and the clearance of Ab across the Blood-Brain Barrier. Mol Med 2011; 17 (3–4): 149–62.
24. Bachmeier C, Beaulieu-Abdelahad D, Mullan M, Paris D. Selective dihydropyiridine compounds facilitate the clearance of beta-amyloid across the blood-brain barrier. Eur J Pharmacol 2011; 659: 124–9.
25. Anekonda TS, Quinn JF. Calcium channel blocking as a therapeutic strategy for Alzheimer's disease. The case for isradipine. Biochim Biophys Acta 2011; 1812: 1584–90.
26. Lopez-Arrieta JM, Birks J. Nimodipine for primary degenerative, mixed and vascular dementia. Cochrane Database Syst Rev 2002. CD000147.
27. Facchinetti F, Fasolato C, Del Giudice E et al. Nimodipine selectively stimulates beta-amyloid 1–42 secretion by a mechanism independent of calcium influx blockage. Neurobiol Aging 2006; 27: 218–27.
28. Zhang L, Yu J, Pan H et al. Small molecule regulators of autophagy identified by an image-based high-throughput screen. Proc Natl Acad Sci USA 2007; 104: 19023–8.
29. Mai A, Valente S, Meade S et al. Study of 1,4-dihydropyridine structural scaffold: discovery of novel sirtuin activators and inhibitors. J Med Chem 2009; 52: 5496–504.
30. Deane R, Yan ShD, Submamaryan RK et al. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med 2003; 9: 907–13.
31. Shibata M al. Clearance of Alzheimer’s amyloid-ss(1–40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest 2000; 106: 1489–99.
32. Gosselet F, Saint-Pol J, Candela P, Fenart L. Amyloid-peptides, Alzheimer's Disease and the Blood-Brain Barrier. Cur Alzheimer Res 2013; 10: 1–19.
33. Bachmeier C, Mullan M, Paris D. Characterization and use of human brain microvascular endothelial cells to examine beta-amyloid exchange in the blood-brain barrier. Cytotechnology 2010; 62: 519–29.
34. Bell RD, Zlokovic BV. Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer’s disease. Acta Neuropathol 2009; 118: 103–13.
35. Deane R, Bell RD, Sagare A, Zlokovic BV. Clearance of amyloid-beta peptide across the blood-brain barrier: implication for therapies in Alzheimer’s disease. CNS Neurol Disord Drug Targets 2009; 8: 16–30.
36. Zlokovic BV, Yamada S, Holtzman D et al. Clearance of amyloid beta-peptide from brain: transport or metabolism? Nat Med 2000; 6: 718–9.
2. Magi S, Castaldo P, Macri ML et al. Intracellular calcium disregulation: implications for Alzheimer’s Disease. Hindawi Publishing Corporation. BioMed Res Int Volume 2016; Article ID 6701324.
3. Forette F et al. Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet 1998; 352: 1347–51.
4. Fritze J, Walden J et al. Clinical findings with nimodipine in dementia: test of the calcium hypothesis. J Neural Transm Suppl 1995; 46: 439–53.
5. Tollefson GD. Short-term effects of the calcium channel blocker nimodipine (Bay-e-9736) in the management of primary degenerative dementia. Biol Psychiatry 1990; 27: 1133–42.
6. Anekonda ThS, Quinn JF, Harris Ch et al. L-type voltage-gated calcium channel blockade with isradipine as a therapeutic strategy for Alzheimer’s disease. Neurobiol Dis 2011; 41 (1): 62–70.
7. Woltjer RL. Role of glutathione in intracellular amyloid-alpha precursor protein/carboxy-terminal fragment aggregation and associated cytotoxicity. J Neurochem 2005; 93: 1047–56.
8. Woltjer RL et al. Effects of chemical chaperones on oxidative stress and detergent-insoluble species formation following conditional expression of amyloid precursor protein carboxy-terminal fragment. Neurobiol Dis 2007; 25: 427–37.
9. Wadsworth TL et al. Evaluation of coenzyme Q as an antioxidant strategy for Alzheimer's disease. J Alzheimers Dis 2008; 14: 225–34.
10. Demuro A, Parker I, Stutzmann G.E. Calcium signaling and amyloid toxicity in Alzheimer disease. J Biol Chem 2010; 285 (17): 12463–8.
11. Berridge MJ. Calcium hypothesis of Alzheimer’s disease. Pflugers Arch – Eur J Physiol. DOI: 10.1007/s00424-009-0736-1
12. Kawahara M, Negishi-Kato M, Sadakane Y. Calcium dyshomeostasis and neurotoxicity of Alzheimer's beta-amyloid protein. Expert Rev Neurother 2009; 9 (5): 681–93.
13. Zhang Y, Li P, Feng J, Wu M. Dysfunction of NMDA receptors in Alzheimer’s disease. Neurol Sci 2016; 37: 1039–47.
14. Toda T, Noda Y, Ito G et al. Presenilin-2 mutation causes early amyloid accumulation and memory impairment in a transgenic mouse model of Alzheimer’s disease. Hindawi Publishing Corporation J Biomed Biotechnol Volume 2011; Article ID 617974.
15. Tu H, Nelson O, Bezprozvanny A et al. Presenilins Form ER Ca2+ Leak Channels, a Function Disrupted by Familial Alzheimer's Disease-Linked Mutations. Alzheimers Dis 2009; 16 (2): 211–24.
16. Xu X. g-Secretase Catalyzes Sequential Cleavages of the AbPP Transmembrane Domain. J Cell 2006; 126 (5): 981–93.
17. Supnet Ch, Bezprozvanny I. The dysregulation of intracellular calcium in Alzheimer disease. Cell Calcium 2010; 47 (2): 183–9.
18. Nussbaum JM, Seward ME, Bloom GS. Alzheimer disease. A tale of two prions. Prion 2013; 7 (1): 14–9.
19. Shu-Ming Huang, Akihiro Mouri, Hideko Kokubo et al. Neprilysin-sensitive synapse-associated amyloid-b peptide oligomers impair neuronal plasticity and cognitive function. J Biol Chem 2006; 281 (26): 17941–51.
20. Eisele Y, Monteiro C, Fearns C et al. Targeting Protein Aggregation for the Treatment of Degenerative Diseases. Nat Rev Drug Discov 2015; 14 (11): 759–80.
21. Forette F et al. The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study. Arch Intern Med 2002; 162: 2046–52.
22. Hanon O, Forette F. Prevention of dementia: lessons from SYST-EUR and PROGRESS. J Neurol Sci 2004; 226: 71–4.
23. Paris D, Bachmeier C, Patel N. Selective antihypertensive dihydropyridines lower Ab accumulation by targeting both the production and the clearance of Ab across the Blood-Brain Barrier. Mol Med 2011; 17 (3–4): 149–62.
24. Bachmeier C, Beaulieu-Abdelahad D, Mullan M, Paris D. Selective dihydropyiridine compounds facilitate the clearance of beta-amyloid across the blood-brain barrier. Eur J Pharmacol 2011; 659: 124–9.
25. Anekonda TS, Quinn JF. Calcium channel blocking as a therapeutic strategy for Alzheimer's disease. The case for isradipine. Biochim Biophys Acta 2011; 1812: 1584–90.
26. Lopez-Arrieta JM, Birks J. Nimodipine for primary degenerative, mixed and vascular dementia. Cochrane Database Syst Rev 2002. CD000147.
27. Facchinetti F, Fasolato C, Del Giudice E et al. Nimodipine selectively stimulates beta-amyloid 1–42 secretion by a mechanism independent of calcium influx blockage. Neurobiol Aging 2006; 27: 218–27.
28. Zhang L, Yu J, Pan H et al. Small molecule regulators of autophagy identified by an image-based high-throughput screen. Proc Natl Acad Sci USA 2007; 104: 19023–8.
29. Mai A, Valente S, Meade S et al. Study of 1,4-dihydropyridine structural scaffold: discovery of novel sirtuin activators and inhibitors. J Med Chem 2009; 52: 5496–504.
30. Deane R, Yan ShD, Submamaryan RK et al. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med 2003; 9: 907–13.
31. Shibata M al. Clearance of Alzheimer’s amyloid-ss(1–40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest 2000; 106: 1489–99.
32. Gosselet F, Saint-Pol J, Candela P, Fenart L. Amyloid-peptides, Alzheimer's Disease and the Blood-Brain Barrier. Cur Alzheimer Res 2013; 10: 1–19.
33. Bachmeier C, Mullan M, Paris D. Characterization and use of human brain microvascular endothelial cells to examine beta-amyloid exchange in the blood-brain barrier. Cytotechnology 2010; 62: 519–29.
34. Bell RD, Zlokovic BV. Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer’s disease. Acta Neuropathol 2009; 118: 103–13.
35. Deane R, Bell RD, Sagare A, Zlokovic BV. Clearance of amyloid-beta peptide across the blood-brain barrier: implication for therapies in Alzheimer’s disease. CNS Neurol Disord Drug Targets 2009; 8: 16–30.
36. Zlokovic BV, Yamada S, Holtzman D et al. Clearance of amyloid beta-peptide from brain: transport or metabolism? Nat Med 2000; 6: 718–9.
________________________________________________
2. Magi S, Castaldo P, Macri ML et al. Intracellular calcium disregulation: implications for Alzheimer’s Disease. Hindawi Publishing Corporation. BioMed Res Int Volume 2016; Article ID 6701324.
3. Forette F et al. Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet 1998; 352: 1347–51.
4. Fritze J, Walden J et al. Clinical findings with nimodipine in dementia: test of the calcium hypothesis. J Neural Transm Suppl 1995; 46: 439–53.
5. Tollefson GD. Short-term effects of the calcium channel blocker nimodipine (Bay-e-9736) in the management of primary degenerative dementia. Biol Psychiatry 1990; 27: 1133–42.
6. Anekonda ThS, Quinn JF, Harris Ch et al. L-type voltage-gated calcium channel blockade with isradipine as a therapeutic strategy for Alzheimer’s disease. Neurobiol Dis 2011; 41 (1): 62–70.
7. Woltjer RL. Role of glutathione in intracellular amyloid-alpha precursor protein/carboxy-terminal fragment aggregation and associated cytotoxicity. J Neurochem 2005; 93: 1047–56.
8. Woltjer RL et al. Effects of chemical chaperones on oxidative stress and detergent-insoluble species formation following conditional expression of amyloid precursor protein carboxy-terminal fragment. Neurobiol Dis 2007; 25: 427–37.
9. Wadsworth TL et al. Evaluation of coenzyme Q as an antioxidant strategy for Alzheimer's disease. J Alzheimers Dis 2008; 14: 225–34.
10. Demuro A, Parker I, Stutzmann G.E. Calcium signaling and amyloid toxicity in Alzheimer disease. J Biol Chem 2010; 285 (17): 12463–8.
11. Berridge MJ. Calcium hypothesis of Alzheimer’s disease. Pflugers Arch – Eur J Physiol. DOI: 10.1007/s00424-009-0736-1
12. Kawahara M, Negishi-Kato M, Sadakane Y. Calcium dyshomeostasis and neurotoxicity of Alzheimer's beta-amyloid protein. Expert Rev Neurother 2009; 9 (5): 681–93.
13. Zhang Y, Li P, Feng J, Wu M. Dysfunction of NMDA receptors in Alzheimer’s disease. Neurol Sci 2016; 37: 1039–47.
14. Toda T, Noda Y, Ito G et al. Presenilin-2 mutation causes early amyloid accumulation and memory impairment in a transgenic mouse model of Alzheimer’s disease. Hindawi Publishing Corporation J Biomed Biotechnol Volume 2011; Article ID 617974.
15. Tu H, Nelson O, Bezprozvanny A et al. Presenilins Form ER Ca2+ Leak Channels, a Function Disrupted by Familial Alzheimer's Disease-Linked Mutations. Alzheimers Dis 2009; 16 (2): 211–24.
16. Xu X. g-Secretase Catalyzes Sequential Cleavages of the AbPP Transmembrane Domain. J Cell 2006; 126 (5): 981–93.
17. Supnet Ch, Bezprozvanny I. The dysregulation of intracellular calcium in Alzheimer disease. Cell Calcium 2010; 47 (2): 183–9.
18. Nussbaum JM, Seward ME, Bloom GS. Alzheimer disease. A tale of two prions. Prion 2013; 7 (1): 14–9.
19. Shu-Ming Huang, Akihiro Mouri, Hideko Kokubo et al. Neprilysin-sensitive synapse-associated amyloid-b peptide oligomers impair neuronal plasticity and cognitive function. J Biol Chem 2006; 281 (26): 17941–51.
20. Eisele Y, Monteiro C, Fearns C et al. Targeting Protein Aggregation for the Treatment of Degenerative Diseases. Nat Rev Drug Discov 2015; 14 (11): 759–80.
21. Forette F et al. The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study. Arch Intern Med 2002; 162: 2046–52.
22. Hanon O, Forette F. Prevention of dementia: lessons from SYST-EUR and PROGRESS. J Neurol Sci 2004; 226: 71–4.
23. Paris D, Bachmeier C, Patel N. Selective antihypertensive dihydropyridines lower Ab accumulation by targeting both the production and the clearance of Ab across the Blood-Brain Barrier. Mol Med 2011; 17 (3–4): 149–62.
24. Bachmeier C, Beaulieu-Abdelahad D, Mullan M, Paris D. Selective dihydropyiridine compounds facilitate the clearance of beta-amyloid across the blood-brain barrier. Eur J Pharmacol 2011; 659: 124–9.
25. Anekonda TS, Quinn JF. Calcium channel blocking as a therapeutic strategy for Alzheimer's disease. The case for isradipine. Biochim Biophys Acta 2011; 1812: 1584–90.
26. Lopez-Arrieta JM, Birks J. Nimodipine for primary degenerative, mixed and vascular dementia. Cochrane Database Syst Rev 2002. CD000147.
27. Facchinetti F, Fasolato C, Del Giudice E et al. Nimodipine selectively stimulates beta-amyloid 1–42 secretion by a mechanism independent of calcium influx blockage. Neurobiol Aging 2006; 27: 218–27.
28. Zhang L, Yu J, Pan H et al. Small molecule regulators of autophagy identified by an image-based high-throughput screen. Proc Natl Acad Sci USA 2007; 104: 19023–8.
29. Mai A, Valente S, Meade S et al. Study of 1,4-dihydropyridine structural scaffold: discovery of novel sirtuin activators and inhibitors. J Med Chem 2009; 52: 5496–504.
30. Deane R, Yan ShD, Submamaryan RK et al. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med 2003; 9: 907–13.
31. Shibata M al. Clearance of Alzheimer’s amyloid-ss(1–40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest 2000; 106: 1489–99.
32. Gosselet F, Saint-Pol J, Candela P, Fenart L. Amyloid-peptides, Alzheimer's Disease and the Blood-Brain Barrier. Cur Alzheimer Res 2013; 10: 1–19.
33. Bachmeier C, Mullan M, Paris D. Characterization and use of human brain microvascular endothelial cells to examine beta-amyloid exchange in the blood-brain barrier. Cytotechnology 2010; 62: 519–29.
34. Bell RD, Zlokovic BV. Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer’s disease. Acta Neuropathol 2009; 118: 103–13.
35. Deane R, Bell RD, Sagare A, Zlokovic BV. Clearance of amyloid-beta peptide across the blood-brain barrier: implication for therapies in Alzheimer’s disease. CNS Neurol Disord Drug Targets 2009; 8: 16–30.
36. Zlokovic BV, Yamada S, Holtzman D et al. Clearance of amyloid beta-peptide from brain: transport or metabolism? Nat Med 2000; 6: 718–9.
Авторы
Е.И.Асташкин
ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М.Сеченова» Минздрава России. 119991, Россия, Москва, ул. Трубецкая, д. 8, стр. 1
ast-med@mail.ru
I.M.Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation. 119991, Russian Federation, Moscow, ul. Trubetskaia, d. 8, str. 1
ast-med@mail.ru
ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М.Сеченова» Минздрава России. 119991, Россия, Москва, ул. Трубецкая, д. 8, стр. 1
ast-med@mail.ru
________________________________________________
I.M.Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation. 119991, Russian Federation, Moscow, ul. Trubetskaia, d. 8, str. 1
ast-med@mail.ru
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