Scientists propose a new theory for the pathogenesis of Alzheimer's disease
BMJ 2001; 322 doi: https://doi.org/10.1136/bmj.322.7294.1085 (Published 05 May 2001) Cite this as: BMJ 2001;322:1085All rapid responses
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Scott Gottlieb has made an important contribution to our knowledge of
AD. The soluble toxic chemical idea and the toxic protein idea should be
vigourously explored.
Much work on not the Amyloid peptides/protein but the Tau protein shows
that organophosphorus molecules attach to the protein molecule and cause
it to lose its shape - ie tangle.
Removal of the organophosphorus from the protein causes it to assume its
original shape. At least 5 molecules of OP are needed to deform the
protein. What is not clear from the research is the source of this "rogue"
OP. If we hazard a guess that AD has risen from a rare disease to very
common in tandem with the use of OP molecules for insecticidal use and
assume that far from being environmentally friendly that they are
persistant as was and is the case for DDT and other Organochlorine (OC)
molecules - we are probably all harbouring circa 12 ppm of OP pesticide
residues. Enough to cause the fatal degeneration of our nerves in our
brains by the age of 80 should we live that long.
The standard preparation of microbiological slides will of course lose the
soluble and offending OP molecules. Hence the reason possibly for the
strange appearance of vacuoles in certain slides of nervous degenerative
illness?
We need to be a little cleverer in our search for the cause of AD and
Scott Gottlieb has made an important step in this search for the cause of
what surely is an environmental illness?
My candidate molecule for harm is Diethyl Phosphate a break down product
from ethyl phosphate insecticides such as Diazinon much used from Jan 1st
1985 for sheep dipping twice a year and in my opinion a contributory
factor in the BSE illness. Most BSE cattle were on sheep pastures or had
other OP contact eg from intervention wheat OP treated to the point where
it was passed as unfit for human but fit for cattle consumption.
This chemical (diazinon) was suspended from use for such purpose on Jan
1st 2000 and on December 5th 2000 the chemical was withdrawn from use
worldwide over a period of the next four years by agreement with the
manufacturer and the CDC in USA.
There are other many very simple breakdown products from OP insecticides
and the work and research on them is skimpy - believed to be harmless
breakdown products and not the candidate molecules for causation of AD.
Is this the cause of AD or is it just another blind alley?
We need to find for sure what chemicals will phosphorylate the tau protein
and there are many to consider from OP insecticides and their metabolites.
The OP toxic molecules do occur naturally in nature and provide a pathway
for the natural production of rogue protein as is found in a few places
worldwide, notably in Guam for example.
John Fryer
Analytical Chemist
Competing interests: No competing interests
Alzheimer's pathogenesis: tau and amyloid - a consensus or a challenge for a third party quest?
To add to the
discussion on Alzheimer's pathogenesis (see BMJ
2001; 322: 1085News Roundup) we would like to attract
readers attention to very recent Science magazinecommentary
article "Tauists and baptists United - Well
Almost" accompanying two studies by Lewis
et.
al. and Gotz
et.al.,
assaying possible pathologic relation between amyloid beta protein and
tau.
We would like to point out that some neurodegenerative diseases, characterized
by both tau tangles and amyloid beta deposition, represent neuronal cholesterol
pathologies, the primary example being Niemann-Pick type C disease [ 1
].
Faulty brain cholesterol dynamics is a minimal requirement causing both
tau and amyloid beta neurochemistry change in genetically naive lab animals,
brain slices and cell cultures (see [ 1,
2
] for details).
As it was proposed [ 3
], experimentally addressed and discussed [ 1
], the change in both tau and amyloid beta protein neurochemistry may independently
help to recover synaptic function and plasticity, the prime neurodegeneration
aim, impaired by neuronal cholesterol turnover misregulation [ 1,
4
].
In our view both understanding brain cholesterol dynamics associated
with learning, memory and cholesterol-lowering medicine (see BMJ
2000; 321: 1241 ), and proposed in Science
commentary the study of transgenic mouse models containing amyloid
and tau pathologies, have legacy to contribute to further elucidation tau-amyloid
pathophysiological relation and primacy.
References:
1. Koudinov AR, Koudinova NV. Essential role
for cholesterol in synaptic plasticity and neuronal degeneration. FASEB
J. published June 27, 2001, 10.1096/fj.00-0815fje [ PubMed
Citation ] [ Abstract
and Full text at FASEB J ] [ Authors
WEB site ] [ Authors
WEB site mirror ] [ Authors
related BMJ Electronic Response ].
2. Fan QW, Yu W, Senda T, Yanagisawa K, and
Michikawa, M. (2001) Cholesterol-dependent modulation of tau phosphorylation
in cultured neurons. J. Neurochem.76, 391-400 [ PubMed
citation ] [ Abstract
and Full Text at J Neurochem ]
3. Mesulam MM. (1999) Neuroplasticity failure
in Alzheimer's disease: bridging the gap between plaques and tangles. Neuron.
24,
521-529. [ PubMed
citation ] [ Full
Text at Neuron ].
4. Matthies H, Schulz S, Hollt V, and Krug
M. (1997) Inhibition by compactin demonstrates a requirement of isoprenoid
metabolism for long-term potentiation in rat hippocampal slices. Neurosci.79,
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and Full Text at Neuroscience ].
Competing interests: No competing interests