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Questions are always good. A dogma is bad. Please help us to eradicate one.
- Alexei R. Koudinov, Natalia V. Koudinova (22 June 2002)
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Amyloid hypothesis: summer 2002 and 8th International Conference on Alzheimer’s disease update
- Alexei R. Koudinov, Natalia V Koudinova (31 July 2002)
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Don't throw in the towel yet on the Amyloid/Alzheimer's hypothesis
- Eric A. Price (27 August 2002)
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Alexei R. Koudinov, neuroscientist Berezov Academic Lab, Russian Academy of Medical Sciences, Moscow, Russia, Natalia V. Koudinova
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The name of the dogma is "brain amyloid as a primary cause and defining feature of Alzheimer's type neurodegeneration". We would like to invite readers to see our eLetter on the BMJ neurodegeneration theme issue editorial by Golbe [ 1 ] and our other BMJ letters [ 2 ] that provide extended online bibliography for the subject. So, click, explore, and justify yourself.
Competing interests: none References:
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Alexei R. Koudinov, neuroscientist Berezov Academic Lab, Rus Acad Med Sci, P.O.Box 1665, Rehovot 76100, Israel, Natalia V Koudinova
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Our recent dEbate letter in Science and eLetters in BMJ [ 1 ] commented on the inability of amyloid hypothesis to advance the disease understanding and to provide its’ pathogenic cure. The response of the amyloid hypothesis proponents included a review article in Science (published on July 19, 2002) [ 2 ] and a notice of our Science dEbate letter at the Elan Corporate Satellite Symposia (that held on July 22 evening at Stockholm Grand hotel) of the 8th International Conference on Alzheimer’s disease and Related Disorders (held July 20-25, 2002 at Stockholm Congress Center). Well. The arguments of the amyloid hypothesis proponents are weak. Thus, one of the congress abstracts states that the “neurotoxic effects of synthetic, fibrillar amyloid-b (Ab) protein on cultured neurons suggests a similar role for the protein in Alzheimer’s disease” [ 3 ]. This is not much evidence for fifteen years long amyloid saga. The statement that “more detailed investigations, however, suggest “pre-fibrillar” Ab species may also mediate the observed neurotoxicity” [ 3 ] is the major Alzheimer's congress amyloid dogma "update" also presented in the review article [ 2 ]. This statement is based on a recent Nature article (see Ref.60 in [ 2 ]) and on two duplicated abstracts of the Stockholm meeting [ 4 ]. We had a chance to comment on the Nature study previously [ 5 ]. Particularly, we highlighted the lack of important experimental, discussion and 'competing interest' consideration that could result in the misinterpretation of the Nature article data and the misleading therapeutic perspective. We will appreciate readers' study of the subject in greater details
and reading a number of recent articles by others on the failure of the
amyloid approach [ 6 ]. We hope that this will help
one to realize that the amyloid hypothesis time has passed away.
Competing interests: none References 1. Koudinov et al. Alzheimer's disease and amyloid beta protein. Science. Published online 25 June, 2002 [ FullText ] [ Readers responses ] ; Koudinov & Koudinova. Questions are always good. A dogma is bad. Please help us to eradicate one. BMJ Published online 22 June, 2002 [ FullText ] ; Koudinov & Koudinova. Beware the simplification in defining neurodegenerative diseases. BMJ Published online 24 June, 2002 [ FullText ] [ Other BMJ eLetters by Koudinov ]. 2. Hardy J & Selkoe DJ. The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics. Science 297, 353 (2002) [ PubMed ] ; Get aware of the list of redundant review articles by Selkoe at the following citation: Koudinov & Koudinova. Alzheimer's anti-amyloid vaccination and statins: two approaches, one dogma. The time for change" BMJ. Published online 20 March, 2002 [ FullText ] ; Also see: Selkoe DJ. Alzheimer's disease results from the cerebral accumulation and cytotoxicity of amyloid b-protein: a reanalysis of a therapeutic hypothesis. J Alzheimer's Dis 3, 75 (2001) ; Selkoe DJ. The genetics and molecular pathology of Alzheimer's disease: roles of amyloid and the presenilins. Neurol Clin. 18, 903 (2000) [ PubMed ]; Selkoe DJ.Clearing the brain's amyloid cobwebs. Neuron. 32, 177 (2001) [ PubMed ]. 3. Whalen et al. Protofibrils of Ab with the arctic mutation induce neuritic pathology prior to neuronal cell death. Neurobiol Aging. 23, S191 (2002) [ Abstract No.717 FullText ]. 4. Walsh et al. Cell-derived Ab oligomers potently inhibit hippocampal long-term potentiation in vivo. Neurobiol Aging. 23, S556 (2002) [ Abstract No.2045 FullText ] ; Klyubin et al. Block of long-term potentiation in the CA1 area of rat hippocampus in vivo by oligomeric but not monomeric forms of synthetic and naturally produced b-amyloid protein Neurobiol Aging. 23, S21 (2002) [ Abstract No.83 FullText ]. 5. Koudinov AR, Koudinova NV. Amyloid hypothesis, synaptic function, and Alzheimer’s disease, or Beware: the dogma is revitalized. BMJ. Published online 15 May, 2002 [ Full Text ]. 6. Smith et al. Dangers
of the amyloid-beta vaccination. Acta Neuropathol (Berl) 104,
110
(2002) [ PubMed
]; Bishop et al. Call for Elan to publish Alzheimer's trial details.
Nature416,
677 (2002) [ PubMed
]; Bergmann et al. Alternatives to the suspended Alzheimer's
disease vaccine.
Acta Neuropathol (Berl) 104, 111 (2002)
[ PubMed
]; Smith
et al. Predicting the failure of amyloid-beta vaccine.
Lancet359,
1864 (2002) [ PubMed
]; Munch G, Robinson SR. Potential neurotoxic inflammatory responses to
Abeta vaccination in humans. J Neural Transm. 109, 1081 (2002)
[ PubMed
]; Imbimbo BP. Toxicity of beta-amyloid vaccination in patients with Alzheimer's
disease. Ann Neurol. 51, 794 (2002) [ PubMed
].
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Eric A. Price, Biochemist Merck & Co., Inc. Sumneytown Pike, West Point, PA 19486
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In regard to the 25 June 2002 Science article "Alzheimer's disease and amyloid beta protein." It is interesting how " the failure of the first human Alzheimer's disease (AD) vaccination trial " and " the vaccination failure will hopefully withdraw the amyloid hypothesis" are within the same article and within the same year. I have never known of a single failure to be interpreted as enough counter-evidence of a hypothesis, theory, or dogma as to entirely withdraw it's legitimacy. It is true that amyloid beta has not been directly proven to be the single source of Alzheimer's disease, and indeed if Alzheimer's had a single cause it may have been elucidated years ago. We do know that amyloid beta does play a role, quite possibly a significant one, and this has been known from the very beginning. The article implies that "failure was the result of an ignorance of amyloid beta normal physiological function(s)" and that the inflammation was, in their opinion, due to the reduction of amyloid beta and a dysregulation of the essential roles that it plays in our CNS. CNS inflammation was a possibility all along with a vaccine that enters the brain. I'm sure that was brought up many years before it was even developed. Along the way the data had looked good enough to proceed. Sure, we may not know the exact etiology but many of us and millions of others can't wait. Furthermore, many drugs have been shown to be effective without having knowlege of their exact mechanism of action. I'm sure sailors had no concept of the structure and function of ascorbic acid, but they saw what citrus could do and acted (ate) upon their observations. We still are ignorant of exactly how lithium ion works in mood and depression and it's been prescribed for decades. Futhermore, it is also true that cholesterol, like amyloid beta as was noted,is an essential component of lipoproteins and is involved in "lipid metabolism and membrane dynamics." Drugs to control hypercholesterolemia are widely used and effective. It may, however, be true that the obliteration of amyloid beta may be less favorable than reducing it. The bottom line is that, in my opinion, the unfortunate failure of the amyloid beta vaccine is not grounds for complete withdrawal of the amyloid hypothesis. I also don't believe the amyloid hypothesis is delaying our understanding of the disease. References: All quotes from "Alzheimer's disease and amyloid beta protein" Science, 25 June 2002. |
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