Rapid Responses to:
|
|
Rapid Responses: Rapid Responses published:
-
![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
Amyloid was never clearly implicated in Alzheimer's disease, so look at Abeta from a different angle
- Alexei R. Koudinov (30 November 2002)
-
Alzheimer's disease vaccine danger: take it straightforward, not double-edged
- Alexei R. Koudinov (23 March 2003)
|
|
|||
|
Alexei R. Koudinov, Senior Research Scientist Berezov Acad Lab, Acad Med Sci, Timoshenko 38/27, Moscow 121359, Russia
Send response to journal:
|
Dear Editor, The history seems returning to another helix turn. Four years ago we all were (or pretended to be ?) excited with the news that "Amyloid clearly implicated in Alzheimer's disease" (BMJ (1998) 316: 446 ; BMJ (1998) 317: 102). The major scientific journals supported by major academicians in their major commentaries celebrated the major advance. The PNAS was reporting last year that "after many years of intense research on the etiology and pathogenesis of Alzheimer's disease (AD), the amyloid b (Ab) peptide, the major component of senile plaques, has become a realistic target for developing effective therapies for AD (PNAS (2001) 98: 8931; also see BMJ 30 July 2002)". Two years earlier the advance (or poor peer review? a question remaining not answered) yielded Nature article on Alzheimer's anti-amyloid vaccination (see ref. at BMJ 15 May 2002). The triumph resulted in the development of not validated amyloid hypothesis into an application that was tributed publically by major media agencies (search eLibrary for 'amyloid and vaccine' in newspapers and magazines), and professionally by a major American Academy of Neurology that awarded The Potamkin Prize '2001 to vaccine developer, a scientist from Elan, one of several biotech companies that battle neurodegeneration in Alzheimer's disease. One may be curious what happened to the amyloid hypothesis a year after the vaccination trial collapsed (BMJ, 19 March 2002). These days the major proponent of the decade-long hypothesis Dr. D. Selkoe in his most recent article draws brave perspective that "deciphering the genesis and fate of amyloid b-protein yields novel therapies for Alzheimer disease" (JCI (2002) 110, 1375). This conclusion is similarly present in his another review article just published in an Annual Review journal (1) and in a series of other recent articles by the amyloid cascade followers (2-5). What every article by any amyloid proponent misses is a one or two paragraph(s) on the data that enlighten amyloid b from a different angle to show the missed point. This is what the Uniform Requirements for Manuscripts Submitted to Biomedical Journals and publication ethics require from every author in order to yield fare scientific discussion. The missed point is that not validated amyloid hypothesis is believed to be unjustified dogma and is strongly disagreed with in the contribution by many other scientists (6-10). The major proposal of the refurbished amyloid hypothesis is that "synaptic
dysfunction is caused by diffusible oligomeric assemblies of the amyloid
beta protein" (11, 12). There
are, however, several arguments that are understated (BMJ
15 May 2002).
Ab may serve an essential role in synapse and synaptic plasticity that underlie learning and memory. Thus it was shown that whereas acute treatment of rat hippocampal slices with low concentrations of bath applied peptide Ab1-40 did not change basal synaptic transmission, there was an increase in tetanus induced long-term potentiation (LTP), a synaptic plasticity measure (14). Moreover, Ab1-40 triggered the slow onset long-term potentiation of the NMDA receptor-mediated synaptic currents (15) in the hippocampal slices from young rats, but did not affect the basal AMPA receptor-mediated transmission, resting membrane potential or input resistance of the granule cells. Similar results were presented by Schulz, who showed no effect of Ab1-42 on AMPA currents, and demonstrated the increase of NMDA currents by the peptide (16). This report proposed that Ab peptides (Ab1-42, Ab1-28 and Ab1-40) increase the probability of LTP under the paradigm that induced little LTP in control slices (16). In our own most recent study [just presented as poster session at the 32nd Society for Neuroscience Annual meeting, Orlando, Florida, Nov.7, 2002 (17)] we attempted to dissect out the role for Ab in the synaptic plasticity in brain slices from adult male rat hippocampus under the condition that we characterised previously with regard to cholesterol and phospholipid synthesis. The prolonged maintanance of slices in a test tube for more then twenty hours in our experimental setup preserved synaptic function (input/output curve, a basic measure of synaptic function) but abrogated synaptic plasticity (LTP). Ab protein of the 1-40 aminoacids' molecule length (representing the major form of soluble Ab) rescued LTP while cholesterol synthesis inhibition with a statin abolished the LTP restoration by Ab peptide. Our observation supports previous data on Ab as ‘good’ molecule (14, 15, 16) and further implies an intriguing perspective that Ab protein is a functional player in an activity-dependent cholesterol neurochemical pathways and in synaptic structure-functional plasticity. The finding also corroborates our proposed hypothesis that the change in Ab biochemistry in Alzheimer's disease and related disorders is a functional (but NOT pathologic) compensatory phenomenon aiming to counterbalance impaired cholesterol dynamics and associated neurotransmission and synaptic plasticity (BMJ Clin Med Netprints 27 Nov, 2001). A role for Ab in neural/synaptic structure-functional plasticity [rather then synaptotoxicity of Ab claimed by amyloid proponents (1-5)] is additionally supported by several studies by others, particularly, by an increase of synaptic amyloid precursor protein (APP) with learning capacity in rats (18), a transient increase of synaptic Ab after the perforant pathway lesioning (19, see my comment for this article news story by AlzForum), by neuronal activity dependent secretion of natural Ab (20), and up-regulating a synaptic vesicle protein transcript by Ab1-42 (21). Most important and directly related to the latest version of the amyloid
hypothesis and the derivative therapy perspectives drawn by D.
Selkoe and his colleagues (1-5) are several articles
that show that Ab is a structure-functional
constituent of lipoproteins (see Ref.22 for further
bibliography), and that lipoproteins potently inhibit neural toxicity of
Ab (23, 24,
25).
So, does the history return to another helix turn? No, it doesn't. The synaptic function for Ab plus the Hippocrates principal of 'no harm' (13-21) warrants growing evidence on the amyloid dogma-based therapy failure (7, 9, 10, 13, 27) that will naturally result in the dogma death. The agony of those who cultivated it, however, will unlikely make the passing away peaceful. Competing financial interests: none Sincerely, Alexei Koudinov, MD, PhD
Footnote: Earlier version of this letter was submitted on November 16, 2002 to AlzForum as a comment to November 14, 2002 news item (on Ref.27) and its comment by D.Schenk. References: 1. Selkoe DJ, Schenk D. Alzheimer's
Disease: Molecular Understanding Predicts Amyloid-Based Therapeutics. Annu
Rev Pharmacol Toxicol. Oct 4, 2002 [epub ahead of print] [ PubMed
]; Also see: Schenk D. Opinion: Amyloid-beta immunotherapy
for Alzheimer's disease: the end of the beginning. Nat Rev Neurosci.3,
824-8 (2002) [ PubMed
].
<CTRL><D> to bookmark this page
Competing interests: None declared |
|||
|
|
|||
|
Alexei R. Koudinov, neuroscientist and editor Russian Academy of Medical Sciences, Moscow; Neurobiology of LIpids, POBox 1665 Rehovot 76100 Israel
Send response to journal:
|
Editor, I recently alerted the readership that the "growing evidence on the amyloid dogma-based therapy failure" will be forthcoming (30 Nov 2002, Ref. 1). This week we got another piece of such evidence, a Nature Medicine article [2] that reports on the "neuropathology of human Alzheimer's disease following immunization with amyloid b-peptide". Based on the report Nature news concludes that "autopsy of inflamed brain points to vaccine dangers." [3] In my view the major importance of this report is that Nature [3] and Alzheimer's association [4] come to realise simple fact that tackling amyloid will nor solve an Alzheimer's mystery nor help Alzheimer's victims (see Table 1). What force me to voice my position on the issue and to warn readers is an accompanying commentary entitled "Alzheimer disease's double-edged vaccine" [5]. This commentary begins with no reference statement that "Amyloid-b (Ab)... is thought to be the cause of cognitive decline" in Alzheimer's disease. I believe that there is no support for such statement as it is not confirmed by the currently available evidence. I also agree that these days it may be a problem to provide a related reference for such statement, as the major recent review by a master of the amyloid hypothesis has red label warning flag in the major journal [6, 7, also see Table 1]. I also understand why commentators understate the normal function for amyloid b, that I and my colleagues discussed recently in great details [1, 8]. This oversight, however, is crucial in making the commentary conclusion that "the results provide support for the notion that inflammation against Ab can be both harmful and helpful." For details where such notion (of a vaccine being helpful) may come from, please see my Open letter to the Public Citizen's Health Research Group [8], my earlier letter in BMJ [1], and the commentary bibliography [5]. What I do not agree with is that "this striking case should guide future approaches to immunotherapy" of Alzheimer's disease [5]. I oppositely do see that this striking case is a regretable moment of truth for Alzheimer's disease research. "It's more proof that the best-laid plans of mice [AK: for a special Alzheimer's mice blockbuster story do not miss Ref. 9] and venture capitalists can face considerable delay if a concept gets too far out in front of the science." [10] "And yet, there is considerable cause for hope" [10]
free of an unjustified and expired amyloid dogma [1,
4,
5,
6].
Sincerely, Alexei Koudinov, MD, PhD
References: 1. Koudinov AR. Amyloid was never clearly implicated in Alzheimer's disease, so look at Abeta from a different angle. BMJ online. (30 Nov 2002) [ FullText ]; Koudinov AR, Smith MA, Perry G, Koudinova NV. Alzheimer's disease and amyloid beta protein. Science online. (14 June 2002) [ FullText ]. 2. Nicoll JAR et al. Neuropathology of Alzheimer's disease after immunization with amyloid-beta peptide: a case report. Nat Med, (17 March 2003) doi:10.1038/nm840 [ FullText ]; 3. Check E. Autopsy of inflamed brain points to vaccine dangers. Nature News Service (17 March 2003) [ FullText ]. 4. Gardner A. The Good and Bad of Experimental Alzheimer's Vaccine. Health Scout News (17 March 2003) [ FullText ]. 5. Greenberg SM, Bacskai BJ, Hyman BT. Alzheimer disease's double-edged vaccine. Nat Med (17 March 2003) doi:10.1038/nm847 [ FullText ]. 6. Koudinov A. Letter to Donald Kennedy, Science Editor-in-Chief (28 Feb 2003) [ .PDF FullText ] [ Inform colleague ]; Also see: Koudinov A. Do not undescore the epidemics of the business, too. Science dEbate submission (31 Jan 2003) [ .PDF FullText ]. 7. Koudinov A. Open letter to Public Citizen's Health Research Group on Alzheimer's disease research. SAGE KE, BMJ (21, 27 Feb 2003) [ BMJ FullText ] [ SAGE KE FullText ]; Also see: Koudinov AR. Ethical conundrums: an Alzheimer's case. British Medical Journal (12 Sept 2002) [ FullText ]. 8. Koudinova NV, Kontush A, Berezov TT, Koudinov AR. Amyloid beta, neural lipids, cholesterol and Alzheimer's disease. Neurobiol. Lipids 1, 6 (3 March 2003) Available at: http://neurobiologyoflipids.org/content/1/6/ [ FullText ]. 9. Dalton R. Researchers caught in dispute over transgenic mice patents. Nature (23 March 2000) 404, 319-20 [ PubMed ] [ FullText ]; Younkin SG, Stoddard S. Nature (20 April 2000) 404, 809 [ PubMed ] [ FullText ]; Dalton R. Patent suit on Alzheimer's mouse rejected. Nature (29 June 2000) 405, 989 [ PubMed ] [ FullText ]; Dalton R. ...but controversy over rights lingers on. Nature (29 June 2000) 405, 989 [ FullText ]. 10. Goldman B. Alzheimer's Disease: The tangled challenge. Signals magazine (3 Dec 1998) [ FullText ]. Competing financial interests: I do not have any competing financial interest. I aim free information dissemination and an unbiased development of Alzheimer's neuroscience. I also aim to restore public confidence in Alzheimer's disease research [8]. I observe the SfN Guidelines for Responsible Conduct Regarding Scientific Communication. Competing interests: None declared |
|||