Acute dosing of latrepirdine (Dimebon?, a possible Alzheimer therapeutic, elevates extracellular amyloid-β levels in vitro and in vivo
详细信息 查看全文
- 作者：John W Steele (1)
Soong H Kim (1)
John R Cirrito (2)
Deborah K Verges (2)
Jessica L Restivo (2)
David Westaway (3)
Paul Fraser (4)
Peter St George Hyslop (4) (5)
Mary Sano (6) (7)
Ilya Bezprozvanny (8)
Michelle E Ehrlich (9)
David M Holtzman (2)
Sam Gandy (1) (7) - 刊名：Molecular Neurodegeneration
- 出版年：2009
- 出版时间：December 2009
- 年：2009
- 卷：4
- 期：1
- 全文大小：1836KB
- 参考文献：1. Gandy S: The role of cerebral amyloid beta accumulation in common forms of Alzheimer disease. / J Clin Invest 2005,115(5):1121-129.
2. Cleary JP, Walsh DM, Hofmeister JJ, Shankar GM, Kuskowski MA, Selkoe DJ, Ashe KH: Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. / Nat Neurosci 2005,8(1):79-4. CrossRef
3. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ: Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. / Nat Med 2008,14(8):837-42. CrossRef
4. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ: Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. / Nature 2002,416(6880):535-39. CrossRef
5. Walsh DM, Klyubin I, Fadeeva JV, Rowan MJ, Selkoe DJ: Amyloid-beta oligomers: their production, toxicity and therapeutic inhibition. / Biochem Soc Trans 2002,30(4):552-57. CrossRef
6. Podlisny MB, Ostaszewski BL, Squazzo SL, Koo EH, Rydell RE, Teplow DB, Selkoe DJ: Aggregation of secreted amyloid beta-protein into sodium dodecyl sulfate-stable oligomers in cell culture. / J Biol Chem 1995,270(16):9564-570. CrossRef
7. Walsh DM, Tseng BP, Rydel RE, Podlisny MB, Selkoe DJ: The oligomerization of amyloid beta-protein begins intracellularly in cells derived from human brain. / Biochemistry 2000,39(35):10831-0839. CrossRef
8. Wild-Bode C, Yamazaki T, Capell A, Leimer U, Steiner H, Ihara Y, Haass C: Intracellular generation and accumulation of amyloid beta-peptide terminating at amino acid 42. / J Biol Chem 1997,272(26):16085-6088. CrossRef
9. Muresan V, Varvel NH, Lamb BT, Muresan Z: The cleavage products of amyloid-beta precursor protein are sorted to distinct carrier vesicles that are independently transported within neurites. / J Neurosci 2009,29(11):3565-578. CrossRef
10. Wirths O, Bayer TA: Alpha-synuclein, Abeta and Alzheimer's disease. / Prog Neuropsychopharmacol Biol Psychiatry 2003,27(1):103-08. CrossRef
11. Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, Seely L, Hung D, Dimebon investigators: 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 2008,372(9634):207-15. CrossRef
12. Reddy PH, Mao P, Manczak M: Mitochondrial structural and functional dynamics in Huntington's disease. / Brain Res Rev 2009,61(1):33-8. CrossRef
13. Bachurin S, Bukatina E, Lermontova N, Tkachenko S, Afanasiev A, Grigoriev V, Grigorieva I, Ivanov Y, Sablin S, Zefirov N: Antihistamine agent Dimebon as a novel neuroprotector and a cognition enhancer. / Ann N Y Acad Sci 2001, 939:425-35. CrossRef
14. Lermontova NN, Lukoyanov NV, Serkova TP, Lukoyanova EA, Bachurin SO: Dimebon improves learning in animals with experimental Alzheimer's disease. / Bull Exp Biol Med 2000,129(6):544-46. CrossRef
15. Lermontova NN, Redkozubov AE, Shevtsova EF, Serkova TP, Kireeva EG, Bachurin SO: Dimebon and tacrine inhibit neurotoxic action of beta-amyloid in culture and block L-type Ca(2+) channels. / Bull Exp Biol Med 2001,132(5):1079-083. CrossRef
16. Wu J, Li Q, Bezprozvanny I: Evaluation of Dimebon in cellular model of Huntington's disease. / Mol Neurodegener 2008, 3:15. CrossRef
17. Grigorev VV, Dranyi OA, Bachurin SO: Comparative study of action mechanisms of dimebon and memantine on AMPA- and NMDA-subtypes glutamate receptors in rat cerebral neurons. / Bull Exp Biol Med 2003,136(5):474-77. CrossRef
18. Bachurin SO, Shevtsova EP, Kireeva EG, Oxenkrug GF, Sablin SO: Mitochondria as a target for neurotoxins and neuroprotective agents. / Ann N Y Acad Sci 2003, 993:334-4. discussion 345- CrossRef
19. Gandy SE, Caporaso GL, Buxbaum JD, de Cruz Silva O, Iverfeldt K, Nordstedt C, Suzuki T, Czernik AJ, Nairn AC, Greengard P: Protein phosphorylation regulates relative utilization of processing pathways for Alzheimer beta/A4 amyloid precursor protein. / Ann N Y Acad Sci 1993, 695:117-21. CrossRef
20. Small SA, Gandy S: Sorting through the cell biology of Alzheimer's disease: intracellular pathways to pathogenesis. / Neuron 2006,52(1):15-1. CrossRef
21. Gouras GK, Xu H, Jovanovic JN, Buxbaum JD, Wang R, Greengard P, Relkin NR, Gandy S: Generation and regulation of beta-amyloid peptide variants by neurons. / J Neurochem 1998,71(5):1920-925. CrossRef
22. Dziewczapolski G, Glogowski CM, Masliah E, Heinemann SF: Deletion of the alpha7 nicotinic acetylcholine receptor gene improves cognitive deficits and synaptic pathology in a mouse model of Alzheimer's disease. / J Neurosci 2009,29(27):8805-815. CrossRef
23. Gasparini L, Gouras GK, Wang R, Gross RS, Beal MF, Greengard P, Xu H: Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. / J Neurosci 2001,21(8):2561-570.
24. Mattson MP, Chan SL: Dysregulation of cellular calcium homeostasis in Alzheimer's disease: bad genes and bad habits. / J Mol Neurosci 2001,17(2):205-24. CrossRef
25. Thinakaran G, Teplow DB, Siman R, Greenberg B, Sisodia SS: Metabolism of the "Swedish" amyloid precursor protein variant in neuro2a (N2a) cells. Evidence that cleavage at the "beta-secretase" site occurs in the golgi apparatus. / J Biol Chem 1996,271(16):9390-397. CrossRef
26. Kim J, Onstead L, Randle S, Price R, Smithson L, Zwizinski C, Dickson DW, Golde T, McGowan E: Abeta40 inhibits amyloid deposition in vivo. / J Neurosci 2007,27(3):627-33. CrossRef
27. Chishti MA, Yang DS, Janus C, Phinney AL, Horne P, Pearson J, Strome R, Zuker N, Loukides J, French J, Turner S, Lozza G, Grilli M, Kunicki S, Morissette C, Paquette J, Gervais F, Bergeron C, Fraser PE, Carlson GA, George-Hyslop PS, Westaway D: Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695. / J Biol Chem 2001,276(24):21562-1570. CrossRef
28. Tampellini D, Rahman N, Gallo EF, Huang Z, Dumont M, Capetillo-Zarate E, Ma T, Zheng R, Lu B, Nanus DM, Lin MT, Gouras GK: Synaptic activity reduces intraneuronal Abeta, promotes APP transport to synapses, and protects against Abeta-related synaptic alterations. / J Neurosci 2009,29(31):9704-713. CrossRef
29. Weiler IJ, Spangler CC, Klintsova AY, Grossman AW, Kim SH, Bertaina-Anglade V, Khaliq H, de Vries FE, Lambers FA, Hatia F, Base CK, Greenough WT: Fragile X mental retardation protein is necessary for neurotransmitter-activated protein translation at synapses. / Proc Natl Acad Sci USA 2004,101(50):17504-7509. CrossRef
30. Cirrito JR, Kang JE, Lee J, Stewart FR, Verges DK, Silverio LM, Bu G, Mennerick S, Holtzman DM: Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo. / Neuron 2008,58(1):42-1. CrossRef
31. Cao C, Cirrito JR, Lin X, Wang L, Verges DK, Dickson A, Mamcarz M, Zhang C, Mori T, Arendash GW, Holtzman DM, Potter H: Caffeine Suppresses Amyloid-beta Levels in Plasma and Brain of Alzheimer's Disease Transgenic Mice. / J Alzheimers Dis 2009,17(3):681-97.
32. Cirrito JR, May PC, O'Dell MA, Taylor JW, Parsadanian M, Cramer JW, Audia JE, Nissen JS, Bales KR, Paul SM, DeMattos RB, Holtzman DM: In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life. / J Neurosci 2003,23(26):8844-853.
33. Bateman RJ, Munsell LY, Morris JC, Swarm R, Yarasheski KE, Holtzman DM: Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. / Nat Med 2006,12(7):856-61. CrossRef
34. Beeri MS, Schmeidler J, Silverman JM, Gandy S, Wysocki M, Hannigan CM, Purohit DP, Lesser G, Grossman HT, Haroutunian V: Insulin in combination with other diabetes medication is associated with less Alzheimer neuropathology. / Neurology 2008,71(10):750-57. CrossRef
35. Abramov E, Dolev I, Fogel H, Ciccotosto GD, Ruff E, Slutsky I: Amyloid-beta as a positive endogenous regulator of release probability at hippocampal synapses. / Nat Neurosci 2009,12(12):1567-6. CrossRef
36. Brody DL, Magnoni S, Schwetye KE, Spinner ML, Esparza TJ, Stocchetti N, Zipfel GJ, Holtzman DM: Amyloid-beta dynamics correlate with neurological status in the injured human brain. / Science 2008,321(5893):1221-224. CrossRef
37. Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Nishino S, Holtzman DM: Amyloid-{beta} Dynamics Are Regulated by Orexin and the Sleep-Wake Cycle. / Science 2009,326(5955):1005-. CrossRef
38. Puzzo D, Privitera L, Leznik E, Fa M, Staniszewski A, Palmeri A, Arancio O: Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus. / J Neurosci 2008,28(53):14537-4545. CrossRef
39. Yamashita M, Nonaka T, Arai T, Kametani F, Buchman VL, Ninkina N, Bachurin SO, Akiyama H, Goedert M, Hasegawa M: Methylene blue and dimebon inhibit aggregation of TDP-43 in cellular models. / FEBS Lett 2009,583(14):2419-424. CrossRef
40. Iversen SD: Behavioural evaluation of cholinergic drugs. / Life Sci 1997,60(13-4):1145-152. CrossRef - 作者单位：John W Steele (1)
Soong H Kim (1)
John R Cirrito (2)
Deborah K Verges (2)
Jessica L Restivo (2)
David Westaway (3)
Paul Fraser (4)
Peter St George Hyslop (4) (5)
Mary Sano (6) (7)
Ilya Bezprozvanny (8)
Michelle E Ehrlich (9)
David M Holtzman (2)
Sam Gandy (1) (7)
1. Departments of Neurology, Psychiatry and Alzheimer's Disease Research Center, Mount Sinai School of Medicine, New York, NY, 10029, USA
2. Department of Neurology, Hope Center for Neurological Disorders and Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, MO, 63110, USA
3. Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, T6G 2M8, Canada
4. Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, M5S 3H2, Canada
5. Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0XY, UK
6. Department of Psychiatry, and Alzheimer's Disease Research Center, Mount Sinai School of Medicine, New York, NY, 10029, USA
7. Department of Neurology, James J Peters VA Medical Center, Bronx, NY, 10468, USA
8. Department of Physiology, University of Texas Southwestern, Dallas, TX, 75390, USA
9. Departments of Pediatrics and Neurology, and Alzheimer's Disease Research Center, Mount Sinai School of Medicine, New York, NY, 10029, USA
文摘
Background Recent reports suggest that latrepirdine (Dimebon? dimebolin), a retired Russian antihistamine, improves cognitive function in aged rodents and in patients with mild to moderate Alzheimer's disease (AD). However, the mechanism(s) underlying this benefit remain elusive. AD is characterized by extracellular accumulation of the amyloid-β (Aβ) peptide in the brain, and Aβ-lowering drugs are currently among the most popular anti-amyloid agents under development for the treatment of AD. In the current study, we assessed the effect of acute dosing of latrepirdine on levels of extracellular Aβ using in vitro and in vivo experimental systems. Results We evaluated extracellular levels of Aβ in three experimental systems, under basal conditions and after treatment with latrepirdine. Mouse N2a neuroblastoma cells overexpressing Swedish APP were incubated for 6 hr in the presence of either vehicle or vehicle + latrepirdine (500pM-5 μM). Synaptoneurosomes were isolated from TgCRND8 mutant APP-overexpressing transgenic mice and incubated for 0 to 10 min in the absence or presence of latrepirdine (1 μM or 10 μM). Drug-na?ve Tg2576 Swedish mutant APP overexpressing transgenic mice received a single intraperitoneal injection of either vehicle or vehicle + latrepirdine (3.5 mg/kg). Picomolar to nanomolar concentrations of acutely administered latrepirdine increased the extracellular concentration of Aβ in the conditioned media from Swedish mutant APP-overexpressing N2a cells by up to 64% (p = 0.01), while a clinically relevant acute dose of latrepirdine administered i.p. led to an increase in the interstitial fluid of freely moving APP transgenic mice by up to 40% (p = 0.01). Reconstitution of membrane protein trafficking and processing is frequently inefficient, and, consistent with this interpretation, latrepirdine treatment of isolated TgCRND8 synaptoneurosomes involved higher concentrations of drug (1-10 μM) and led to more modest increases in extracellular Aβx-42 levels (+10%; p = 0.001); of note, however, was the observation that extracellular Aβx-40 levels did not change. Conclusions Here, we report the surprising association of acute latrepirdine dosing with elevated levels of extracellular Aβ as measured in three independent neuron-related or neuron-derived systems, including the hippocampus of freely moving Tg2576 mice. Given the reported association of chronic latrepirdine treatment with improvement in cognitive function, the effects of chronic latrepirdine treatment on extracellular Aβ levels must now be determined.