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EDITORIALS: Lawrence I Golbe Neurodegeneration in the age of molecular biology BMJ 2002; 324: 1467-1468 [Full text]

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Alzheimer’s amyloid dogma. A time for change.

Alexei R. Koudinov, Mark A. Smith, George Perry, Natalia V. Koudinova   (21 June 2002)

Alzheimer’s amyloid dogma. A time for change. 21 June 2002
Alexei R. Koudinov, neuroscientist Russian Academy Medical Sciences, Moscow, Russia; Case Western Reserve University, Cleveland OH, USA, Mark A. Smith, George Perry, Natalia V. Koudinova Send response to journal: Re: Alzheimer’s amyloid dogma. A time for change.	Inform a Colleague Disappointing news of the failure of the first human Alzheimer’s disease vaccination trial was not noted in a recent BMJ article [ 1 ] and in today’s BMJ theme issue on neurodegeneration. The goal of the vaccine, made of synthetic amyloid peptide, was to reduce the amyloid load in the brain of patients by means of the body’s immune reaction to clear amyloid deposits. However, perhaps a consequence of doing this, it also caused major complications currently assigned to cerebral inflammation in fifteen of 360 AD patients who had been vaccinated [ 1 ].  These side effects led to the halting of the trial. Unfortunately, this failure was not totally unexpected and knowing exactly how it failed is one of the most important issues today [ 1 ]. In our opinion, failure was the result of an ignorance of amyloid beta normal physiological function(s).  In fact, we would venture that there is no direct evidence on the pathogenic primacy or importance of amyloid beta in Alzheimer’s disease. There is accumulating evidence that amyloid beta is a functional and essential component of brain metabolism. In this regard, amyloid beta is a structural constituent of high density lipoproteins, modulates oxidative mechanisms and is involved in lipid metabolism and membrane dynamics as a regulatory element [ 2, 3 ].   Therefore, it is notable that, despite rumors to the contrary, there is no evidence that the accumulation, oligomerization and aggregation of amyloid beta plays a causal role in the development of the disease. Nonetheless, top biomedical journals add to the dogma that amyloid is detrimental by publishing redundant editorials and review articles supporting this view [ 4 ] and not balancing the discussion by publishing novel and alternative viewpoints.  The role of amyloid beta in lipid (particularly cholesterol) metabolism opens the possibility that abnormal cholesterol dynamics is at the root of Alzheimer’s disease and that therapeutics focused on that route may be efficacious [ 2 ]. The failure of Alzheimer’s “immunotherapy” in our view should now encourage research on physiologically-relevant compensatory mechanisms of neural degeneration and Alzheimer’s disease and related disorders, and on the normal functional biochemistry of amyloid beta [ 2, 5 ]. Further, the vaccination failure will hopefully withdraw the amyloid dogma that has dominated the stage thus delaying our understanding of the disease and the development of efficacious therapeutics for the past fifteen years.    [Inform a Colleague] [Send us an email] <CTRL><D> TO BOOKMARK Competing interests: none References: 1. Check E. Nerve inflammation halts trial for Alzheimer's drug. Nature.  415, 462 (2002) [ PubMed ] [ AlzForum Drug News ] [ AlzForum live discussion ];  Koudinov AR, Koudinova NV. Alzheimer’s anti-amyloid vaccination and statins: two approaches, one dogma. The time for change BMJ Published online 20 March, 2002 [ Full Text ] [ Related eLetters ]; Koudinov AR, Koudinova NV. Amyloid hypothesis, synaptic function, and Alzheimer’s disease,  or Beware: the dogma is revitalized. BMJ Published online 15 May, 2002 [ FullText ]. 2. Chochina SV, Avdulov NA, Igbavboa U, Cleary JP, O'Hare EO, Wood WG. Amyloid beta-peptide(1-40) increases neuronal membrane fluidity. Role of cholesterol and brain region. J Lipid Res.42, 1292-1297 (2001) [ PubMed ] [ Full Text ]; Koudinov AR, Koudinova NV. Essential role for cholesterol in synaptic plasticity and neuronal degeneration. FASEB J. 15, 1858-60 (2001), originally published online June 27, 2001, 10.1096/fj.00-0815fje [ PubMed ] [ Full Text ] [ Post-publication account in Science ] [ Article Preface ] [ Related eLetters ]; Koudinov AR, Koudinova NV. Brain Cholesterol Pathology is the Cause of Alzheimer's Disease. Clin Med Health Res. published online November 27, 2001, clinmed/2001100005  [ Full Text ] [ Authors Preface ]. 3. Kontush A. Amyloid-beta: an antioxidant that becomes a pro-oxidant and critically contributes to Alzheimer's disease. Free Radic Biol Med. 31, 1120-1131 (2001) [ PubMed ]; Bush A. Response: '...and C is for Clioquinol' -- the AbetaCs of Alzheimer's disease. TINS. 25,  123-124 (2002) [ PubMed ]. 4. Golbe LI.  Editorials: Neurodegeneration in the age of molecular biology BMJ  324, 1467-1468 (2002) [ Full Text ]; Taylor JP, Hardy J, Fischbeck KH. Toxic Proteins in Neurodegenerative Disease. Science 296, 1991-1995 (2002) [ PubMed ] [  Full Text ]; Selkoe DJ. Toward a comprehensive theory for Alzheimer's disease. Hypothesis: Alzheimer's disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein. Ann N Y Acad Sci. 924, 17-25 (2000) [ PubMed ]; Selkoe DJ. Translating cell biology into therapeutic advances in Alzheimer's disease Nature. Neurological disorders. 399 (Supplement), A23-A31; Selkoe D. The origins of Alzheimer disease: a is for amyloid. JAMA.283,1615-1617 (2000) [ PubMed ] [ Full Text ]; Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 81, 741-66 (2001) [ PubMed ]. 5. Mesulam MM. Neuroplasticity failure in Alzheimer's disease: bridging the gap between plaques and tangles. Neuron. 24, 521-529 (1999). [ PubMed ] [ Full Text ] [ AlzForum live discussion ]; Smith MA, Drew KL, Nunomura A et al. Amyloid-beta, tau alterations and mitochondrial dysfunction in Alzheimer disease: the chickens or the eggs? Neurochem Int. 40, 527-31 (2002) [ PubMed ]