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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.
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 BMJ324,
1467-1468 (2002) [ Full
Text ]; Taylor JP, Hardy J, Fischbeck KH. Toxic Proteins in Neurodegenerative
Disease. Science296, 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
]
Competing interests:
No competing interests
21 June 2002
Alexei R. Koudinov
neuroscientist
Mark A. Smith, George Perry, Natalia V. Koudinova
Russian Academy Medical Sciences, Moscow, Russia; Case Western Reserve University, Cleveland OH, USA
Alzheimer’s amyloid dogma. A time for change.
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 ].
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.
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. Science296, 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
]
Competing interests: No competing interests