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Hello, AlzClub and AlzheimerCode are not-for-profit web sites for non-censored ideas, news, research, technology and clinics on Alzheimer's disease and related disorders. Both are run personally by me, Alexei Koudinov, MD, PhD, DrSci, well known for his Alzheimer's and basic science research, and for battling against the corruption of Alzheimer's field, to protect public interest. Few examples are under must read links above, most notable of which are correspondence with the Wall Street Journal that yielded three WSJ articles on Alzheimers, Security and Exchange Commission (SEC) and Written Evidence to UK Parliamentary committee. My contrubution to Alzheimer's research is summarized in cholesterol failure theory of Alzheimer's and in the series of publications here. - With love, Alexei Koudinov

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2010/08/17

Lipoprotein-association of Alzheimer’s amyloid beta: a way to preserve phiological soluble state of a amphipathic apoAbeta molecule

This is Part 3 of the unabridged original manuscript, submitted by invitation in April 2009 to the theme issue of The Journal of Alzheimer's disease. Edited by the Journal edition was later published and is available upon request (will be published here at a later date)

Part 1 | Part 2 | Part 3 | Part 4 | Part 5

Alexei Koudinov, Elena Kezlya, Natalia Koudinova, Temirbolat Berezov Amyloid-beta, tau protein, and oxidative changes as a physiological compensatory mechanism to maintain CNS plasticity under Alzheimer's disease and other neurodegenerative conditions. Journal of Alzheimer’s Disease. 2009 18(2): 381-400. Unabridged Notedited Original Author Edition. Available at: http://alzheimercode.blogspot.com

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Part 3 | Part 1 | Part 2

In line with the notion that Abeta is an apolipoprotein constituent of the HDL, we further showed that natural apoAbeta does not cross link with other apoliporoteins in normal CSF HDL (indicating a priority of apoAbeta-to-lipid interaction under normal condition) [[32]] and that an interaction of apoAbeta with apolipoproteins is a characteristic of Alzheimer’s CSF HDL samples [[25]]. In Alzheimer’s, therefore, there is a break of the lipoprotein structural integrity in a way that favors interaction of Abeta-to-Abeta(that creates oligomers [[33]] or apoAbeta-to-other apolipoprotein, shown for ApoE and ApoJ [[25]], and most recently for ApoA1 [[34]].

Of major support for the argument of the “mistaken identity” is the potent inhibition of neural toxicity of Abeta by lipoproteins [[34, 35, 36]], apoA1 and apoE, two major apolipoproteins and lipid binding proteins in the circulation and the brain, respectively [[34, 38]], and a risk factor for AD [[38]]. It is very unfortunate that these facts neither discussed nor experimentally addressed in key experimental [[12, 33]] and recent articles on oligomeric amyloid hypothesis [[13, 14]].

Additionally, there is a major experimental deficiency by oligomeric amyloid hypothesis proponents, and all others, who use “antibodies that can selectively target soluble oligomers of Abeta” [[1, 33]]. We do believe that these antibodies are poorly characterized and therefore may mistake natural lipoprotein-associated soluble apoAbeta (and other membrane-bound proteins) for lipid free Abeta oligomers. This is because micellar Abeta used for production of anti-oligomer antibodies [[33]] may well mimic the conformational motif of lipoprotein-bound apoAbeta and of other membrane-bound proteins [[39]].

Similarly, the experimental lack of the association of Abeta with lipoproteins (that potently arrests Ab neurotoxicity [[34,35,36,37]] questions physiological relevance of the study of the role for oligomers in synapse dysfunction and toxicity [[12,13,14]]. Moreover, it is well documented that “Abeta associat[ion] with membranes is dynamic and capable of adopting a number of conformations, each of which may have significance in understanding the progression of Alzheimer's disease.” [[29, 40]]. It is also shown that experimental Abeta neurotoxicity is modulated by the rate of peptide aggregation [[41]] and neuronal functional state [[42]]. Thus, potassium-induced membrane depolarization, a treatment modeling basic neuronal function, significantly reduced vulnerability to aggregated beta-amyloid peptides of cultured rat hippocampal neurons pretreated with high potassium [[42]]. Therefore, the lack of such a consideration is any experimental protocol on amyloid oligomers can generate a systemic error and lead to wrong conclusions (also see below).

References:


1. SR. Robinson, GM. Bishop, G. Munch. Alzheimer vaccine: amyloid  on trial. Bioessays (2003) 25:283-288.

12. DM. Walsh, I. Klyubin, JV. Fadeeva, WK. Cullen, R. Anwyl, MS. Wolfe, MJ. Rowan, DJ. Selkoe. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature (2002) 416:535-539.

13. Rowan MJ, Klyubin I, Wang Q, Hu NW, Anwyl R (2007) Synaptic memory mechanisms: Alzheimer's disease amyloid beta-peptide-induced dysfunction. Biochem Soc Trans 35(Pt 5), 1219-1223.

14. Selkoe DJ (2008) Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav Brain Res 192(1), 106-113.

25. AR. Koudinov, TT. Berezov, NV. Koudinova. The levels of soluble A in different HDL subfractions distinguish Alzheimer's and normal aging CSF: implication for brain cholesterol pathology? Neurosci Lett. (2001) 314:115-118.


32. AR. Koudinov, TT. Berezov, NV. Koudinova. Alzheimer's amyloid beta protein association with high density lipoprotein in normal human cerebrospinal fluid: primary binding to lipid? Soc. Neurosci. (1997) 23:537.

33. R. Kayed, E. Head, JL. Thompson, TM. McIntire, SC. Milton, CW. Cotman, CG. Glabe. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science (2003) 300:486-489.

34. Paula-Lima AC, Tricerri MA, Brito-Moreira J, Bomfim TR, Oliveira FF, Magdesian MH, Grinberg LT, Panizzutti R, Ferreira ST. Human apolipoprotein A-I binds amyloid-beta and prevents Abeta-induced neurotoxicity. Int. J. Biochem. Cell Biol. (2008 Dec 14) PMID 19130896

35. A. Cedazo-Minguez, M. Huttinger, RF. Cowburn. Beta-VLDL protects against Abeta(1-42) and apoE toxicity in human SH-SY5Y neuroblastoma cells. NeuroReport (2001) 12:201-206.

36. ZS. Farhangrazi, H. Ying, G. Bu, LL. Dugan, AM. Fagan, DW. Choi, DM. Holtzman. High density lipoprotein decreases beta-amyloid toxicity in cortical cell culture. NeuroReport (1997) 8:1127-1130.

37. RP. Koldamova, IM. Lefterov, MI. Lefterova, JS. Lazo. Apolipoprotein A-I directly interacts with amyloid precursor protein and inhibits Abeta aggregation and toxicity. Biochemistry (2001) 40: 3553-3560.

38. JS. Whitson, MP. Mims, WJ. Strittmatter, T. Yamaki, JD. Morrisett, SH. Appel. Attenuation of the neurotoxic effect of Abeta amyloid peptide by apolipoprotein E. Biochem. Biophys. Res. Commun. (1994) 199(1):163-70.

39. B. Soreghan, C. Pike, R. Kayed, W. Tian, S. Milton, C. Cotman, CG. Glabe. The influence of the carboxyl terminus of the Alzheimer Abeta peptide on its conformation, aggregation, and neurotoxic properties. Neuromolecular Med. (2002) 1:81-94

40. JA. Lemkul, DR. Bevan DR. A comparative molecular dynamics analysis of the amyloid beta-peptide in a lipid bilayer. Arch. Biochem. Biophys. (2008) 470(1):54-63.

41. LW. Hung, GD. Ciccotosto, E. Giannakis, DJ. Tew, K. Perez, CL. Masters, R. Cappai, JD. Wade, KJ. Barnham. Amyloid-beta peptide (Abeta) neurotoxicity is modulated by the rate of peptide aggregation: Abeta dimers and trimers correlate with neurotoxicity. J. Neurosci. (2008) 28(46):11950-8.

42. CJ. Pike, R. Balázs, CW. Cotman. Attenuation of beta-amyloid neurotoxicity in vitro by potassium-induced depolarization. J. Neurochem. (1996) 67(4):1774-7

Link to this publication: Alzheimer-amyloid-beta-lipoprotein

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