Amyloid beta oligomers and lipoprotein apoAbeta: mistaken identity well possible, Part 2

This is Part 2 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)

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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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Amyloid beta oligomers and lipoprotein apoAbeta: mistaken identity well possible

For a decade and a half we all know that Abeta is normally produced by cells and exists as normal soluble molecule and that it indeed is an important brain chemical with a diverse function [[reviewed in Ref.17]]. Even a key scientist of AD field, quoted above Dr. Selkoe acknowledged a number of years ago “that Abeta is produced physiologically and may have a normal function, but when it accumulates excessively in certain regions of the brain, it can oligomerize and attain new, potentially neurotoxic functions, as many labs worldwide -- including ours -- have shown. So, Abeta is normal, but it also appears to contribute to disease. Lowering its brain concentrations back to normal levels is one approach to treating and preventing AD. We are certainly not ignoring its physiological role.” [[18]]. Selkoe group was one of those who confirmed A association with the lipoproteins as a circulatory form of Abeta [[19]].

However, sadly and contrary to what Selkoe says, the physiological role for Abeta is largely ignored. We first hand experienced the opposition to deliver our public scientific concern on the validity of amyloid oligomers when attempting to contribute communication arising matter on the article published in Nature [[10, 12, 20]]. Our letter finally was published, but in a different journal, British Medical Journal [[15]]. A key date is March 26, 2003 when Neuron published an article that opened scientific discussion of synaptic function for Abeta and its precursor (APP) in the major neuroscience journal [[21]]. Interestingly, this research by the lab of an accomplished neuroscience leader was published three years after it was first reported at the 32nd Society for Neuroscience Annual Meeting 2000, enlightening the tight opposition by opponents for a public scientific presentation of the data on Abeta physiological function, and well supporting the conclusion of assisted by Dr. Koudinov widely recognized journalistic research by Sharon Beagley, major US-based science journalist (then a WSJ staff science writer) [[2,3,4,5,22]].

Our past study and research by others provided evidence that Abeta is a structure-functional apolipoprotein constituent (apoAbeta) of high density lipoproteins in both blood and cerebrospinal fluid [[23, 24, also see Refs. 17, 25 for detailed bibliography]]. Abeta is also secreted by hepatic cells [[26]] and by the astrocytes [[27]] as a part of lipoprotein complexes [[26, 27]]. Lipoproteins provide a proper thermodynamic environment for Abeta that shares with other apolipoproteins a unique structural property of amphipathicity [[28, 29]]. The amphipathicity explains an association of some apolipoproteins' hydrophobic parts with lipids of the outer layer of lipoprotein particles, and with apolar parts of other apolipoprotein molecules. Another characteristic of amphipathic molecules is the high tendency to self-associate which also takes place during protein oligomerization and amyloid fibril formation. Magnificent experimental evidence indicates that, out of the lipid environment, apolipoproteins are easily subjected to cross- and self- aggregation, oligo- and polymerization [[reviewed in Ref. 28]]. Moreover, some of them form amyloid fibrils and represent separate types of human amyloidosis, ex. apoA-I and serum amyloid A (AA). Interestingly, amyloid story of Alzheimer’ was introduced in 1984 by George Glenner [[30]], who studied different type amyloidoses. Should one carefully research his scientific contribution and legacy, he or she could be impressed by Dr. Glenner dedication and willingness to demonstrate Alzheimer’s is just another amyloid disease in line with other pathologies that he studied previously. Dr. Glenner died in 1995 at the age of 67, he suffered himself of systemic senile amyloidoses [[31]].

Well, Alzheimer’s story is not that simple as amyloid hypothesis proponents are trying to convince others. ...to be continued

References

17. AR. Koudinov, TT. Berezov. Alzheimers amyloid-beta (Abeta) is an essential synaptic protein, not neurotoxic junk. Acta Neurobiologica Exp. (2004) 64(1): 71-79. http://www.nencki.gov.pl/pdf/an/vol64/koudin.pdf

18. Correspondence with Dennis Selkoe. Alexei Koudinov web site (Aug. 2002-July 2004) Available at: http://koudinov.info/archive/selkoe.html

19. AL. Biere, B. Ostaszewski, ER. Stimson, BT. Hyman, JE. Maggio, DJ. Selkoe. Amyloid beta-peptide is transported on lipoproteins and albumin in human plasma. J. Biol. Chem. (1996) 271(51): 32916-22.

20. Correspondence with Nature Editorial office. (April 2002 – Dec. 2002) Available at: http://neurobiologyoflipids.org/editors/alexeikoudinov/pdfdocs/submittedletters/koudinov2nature02.pdf

21. F. Kamenetz, T. Tomita, H. Hsieh, G. Seabrook, D. Borchelt, T. Iwatsubo, S. Sisodia, R. Malinow. APP processing and synaptic function. Neuron (2003) 37:925-937

22. Correspondence with Sharon Begley. Alzclub.org (2003) To be available at: http://www.alzclub.org

23. AR. Koudinov, E. Matsubara, B. Frangione, J. Ghiso. The Soluble form of Alzheimer's amyloid beta protein is complexed to high density lipoprotein 3 and very high density lipoprotein in normal human plasma plasma. Biochem. Biophys. Res. Commun. (1994) 205:1164-1171.

24. AR. Koudinov, NV. Koudinova, A. Kumar, R. Beavis, J. Ghiso. (1996) Biochemical characterization of Alzheimer's soluble amyloid beta protein in human cerebrospinal fluid: association with high density lipoproteins. Biochem. Biophys. Res. Commun. (1996) 223:592-597

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.

26. AR. Koudinov, NV. Koudinova. Soluble amyloid beta protein is secreted by HepG2 cells as an apolipoprotein. Cell. Biol. Inter. (1997) 25:265-271.

27. MJ. Ladu, C Reardon, L Van Eldik, AM. Fagan, G Bu, DM. Holtzman. Lipoproteins in the central nervous system. Ann. NY Acad. Sci. (2000) 903: 167-175.

28. AR. Koudinov, TT. Berezov, A. Kumar, NV. Koudinova. (1998) Alzheimer's amyloid beta interaction with normal human plasma high density lipoprotein: association with apolipoprotein and lipids. Clin. Chim. Acta (1998) 270: 75 –84.

29. AR. Koudinov, NV. Koudinova, TB. Berezov, YuD. Ivanov. HDL Phospholipid: a Natural Inhibitor of Alzheimer's Amyloid beta Fibrillogenesis? Clin. Chem. Lab. Med. (1999) 37: 993-4.

30. GG. Glenner, CW. Wong. (1984) Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. (1984) 120: 885-890.

31. W. Saxon. Dr. George G. Glenner, 67, Dies; Researched Alzheimer's Disease. New York Times. (14 July 1995). Available at: http://query.nytimes.com/gst/fullpage.html?res=990CE5DC1F30F937A25754C0A963958260

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