After amyloid hypothesis of Alhzeimer disease dementia, Part 1

This is Part 1 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 hypothesis dominated the stage of Alzheimer’s disease research for over two decades but failed to explain the pathogenesis of Alzheimer’s disease (AD) or provide neurodegeneration cure. The original formulation of the hypothesis stated that at the origin of Alzheimer’s pathogenesis are the fibrillogenesis of amyloid beta protein (Abeta) and the formation of amyloid plaques that cause synaptic failure and clinical picture of memory loss. Interestingly, vast majority of Abeta experimentation was performed in vitro with the synthetic analogs of heterogeneous Abeta peptides (in terms of molecule length due to amino acid number variations). Also interesting is that despite of claimed abundance in AD brain, human Abeta was never purified in preparative quantities from Alzheimer’s brain sections. In 2002 failed experimental vaccine treatment of Alzheimer’s with antibodies against Abeta [[1]] caused severe brain inflammation in a significant number of patients, worthening of AD symptoms and patients’ death. This was the time of the first major public criticism of amyloid hypothesis and AD field. Two years later, Sharon Begley of the major international Wall Street Journal (WSJ) with the assistance of a number of premier scientists worldwide concluded in a series of the WSJ Science magazine [[2,3,4,5]] that over the years amyloid hypothesis has become dogma that retarded the development of the entire field for more then a decade. At the same time the hypothesis was challenged by a number of Alzheimer’s neuroscience research groups and finest science journalists worldwide [[2,3,4,5,6,7,8,9]]. Moreover, UK Parliament hearing [[10]] reported on the competing financial interest by a number of key players of AD field and science and professional establishment (such as American Academy of Neurology [[11]]), and uncovered the sad role of major STM journals (ex., Science, Nature, Neuron) in retarding the publication of alternative Alzheimer’s theories [[10]].

Yet, the pharmaceutical industry research is still dominated by amyloid hypothesis, primarily through the usage of mutant Abeta transgenic mice as a “gold standard” animal model for testing prospective Alzheimers therapies.

In reply on a challenge, amyloid proponents refurbished their big bucks backed argument. The latest edition of the amyloid theory states that the major AD culprit are amyloid beta oligomers [[12]]. They particularly say that “there is growing evidence that mild cognitive impairment in early AD may be due to synaptic dysfunction caused by the accumulation of non-fibrillar, oligomeric Abeta (amyloid beta-peptide), long before widespread synaptic loss and neurodegeneration occurs. Soluble Abeta oligomers can rapidly disrupt synaptic memory mechanisms at extremely low concentrations via stress-activated kinases and oxidative/nitrosative stress mediators.” [[13]]. In his latest review article, Dennis Selkoe of Harvard says that "during the last 25 years, neuropathological, biochemical, genetic, cell biological and even therapeutic studies in humans have all supported the hypothesis that the gradual cerebral accumulation of soluble and insoluble assemblies of the amyloid beta-protein in limbic and association cortices triggers a cascade of biochemical and cellular alterations that produce the clinical phenotype of Alzheimer's disease." [[14]]. He adds, that “the reasons for elevated cortical Abeta levels in most patients with typical, late-onset AD are unknown, but… these could turn out to include augmented neuronal release of Abeta during some kinds of synaptic activity”. He thus allows physiological function for Abeta, but apparently is hesitant to discuss it publicly in greater details. “Elevated levels of soluble Abeta42 monomers enable formation of soluble oligomers that can diffuse into synaptic clefts, …can disrupt hippocampal LTP in slices and in vivo and can also impair the memory of a complex learned behavior in rats,” Selkoe concludes [[14]].

Lacking-since-inauguration is the possibility that Abeta oligomers are experimental artifacts [[12, 15]]. This is because missed is the pivotal consideration that as a lipoprotein structural component, Abeta molecule gets easy amyloidogenic oligomerization out of lipid environment. Association of Abeta with high density lipoproteins (HDL) in plasma and cerebrospinal fluid (CSF) was first demonstrated by us in early 1990s [[16]], confirmed by many groups since then, and is an apparent structural reason for Abeta involvement in lipid metabolism, as outlined below. ...To be continued

References:

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

2. S. Begley. Is Alzheimer's Field Blocking Research Into Other Causes? The Wall Street Journal (9 April 2004) p.B.1
http://online.wsj.com/article/SB108145279348578177.html

3. S. Begley. Scientists World-Wide Battle a Narrow View Of Alzheimer's Cause.
The Wall Street Journal (16 April 2004) p.A.9
http://online.wsj.com/article/SB108206188684384119.html

4. S Begley. Fevered Debate Over Alzheimer's Origins Causes Deep Divisions. The Wall Street Journal (6 August 2004) p.B.1 http://neurobiologyoflipids.org/news/news2004.html#wsj060804

5. RW. Mahley, S Goldberg, RJ. Hodes. Does Bias Confound Alzheimer's Research? The Wall Street Journal (27 April 2004) p.A.19 http://neurobiologyoflipids.org/news/news2004.html#wsj

6. Bishop GM, Robinson SR, Smith MA, Perry G, Atwood CS. Call for Elan to publish Alzheimer's trial details. Nature. 2002 Apr 18;416(6882):672704047.

7. AR. Koudinov, MA. Smith, G. Perry, NV. Koudinova. Alzheimer's disease and amyloid beta protein. Science (25 June 2002) Available at: http://www.sciencemag.org/cgi/eletters/296/5575/1991

8. Correspondence with Geoffrey Cowley, Newsweek Health and Science reporter (2003) To be available at: http://alzheimercode.blogspot.com

9. Crowley D. (16 Nov 2003) Selkoe's sale of Elan shares referred to SEC. Sunday Times. Available at: http://www.timesonline.co.uk/article/0,,2095-895532,00.html

10. Koudinov AR. Part 1: Editorial and publisher corruption. Written evidence for inquiry on Scientific Publication by Science and Technology Committee, UK House of Commons. (2004) Available at: http://www.publications.parliament.uk/pa/cm200304/cmselect/cmsctech/399/399we125.htm Also available at: http://neurobiologyoflipids.org/editors/alexeikoudinov/pdfdocs/submittedletters/koudinovwrittenevidence.pdf

11. Correspondence with Murray Sagsveen, General Counsel and Associate Executive Director, American Academy of Neurology (AAN). (Nov. 2002-March 2003) Available at: http://neurobiologyoflipids.org/editors/alexeikoudinov/pdfdocs/submittedletters/koudinov2aansagsveennov02march03.pdf

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.

15. AR. Koudinov, NV. Koudinova. Amyloid hypothesis, synaptic function, and Alzheimer’s disease, or Beware: the dogma is revitalized. British Medical J. (2002) Available at: http://bmj.com/cgi/eletters/324/7338/656


16. NV. Koudinova, A. Kontush, TT. Berezov, AR. Koudinov. Amyloid beta, neural lipids, cholesterol and Alzheimer's disease. Neurobiology Lipids (2003) 1:6. Available at: http://neurobiologyoflipids.org/content/1/6/

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