Subject:           [AVN] Re: Is Alzheimer's field blocking R&D into other causes?
     Date:           Wed, 14 Apr 2004 21:20:42 +0100
    From:           Sheri Nakken <vaccineinfo@tesco.net>
 Reply-To:           AVN@yahoogroups.com
       To:           Sheri Nakken <vaccineinfo@tesco.net>

>From Boyd Haley with permisssion to share

Sheri:  This is exactly correct.  When I submitted for a renewal a NIH 
grant that I had on the tubulin disfunction (which could be mimicked by 
mercury and only mercury exposure when I tested a large number of toxicants 
that humans might be exposed to) the killing remark in the review was "how 
does this relate to amyloid?"  A further comment on one of my reviews was 
close to "Dr. Haley has to realize that we have seen enough of this type of 
research."  They were referring to using my photoaffinity labeling 
technology to show that certain metals could affect the tubulin disfunction 
as seen in AD brain, mercury being by far the most effective.  Finally, a 
publication ( Olivieri, et al  Mercury Induces Cell Cytotoxicity and 
Oxidative Stress and Increases ?-amyloid Secretion and Tau Phosphorylation 
in SHSY5Y Neuroblastoma Cells.  J. Neurochemistry 74, 231-231, 2000.) 
reported that exposure of neuroblastoma cells with nanomolar mercury 
increased the production of beta-amyloid protein, which makes up the 
amyloid plaque, and increased the hyperphosphorylation of tau (also a 
marker for AD).  Additionally, others (Leong, CCW, Syed, N.I., and 
Lorscheider, F.L.  Retrograde Degeneration of Neurite Membrane Structural 
Integrity and Formation of Neruofibillary Tangles at Nerve Growth Cones 
Following In Vitro Exposure to Mercury.  NeuroReports 12 (4):733-737, 2001) 
showed by filming that mercury, and only mercury, stripped the tubulin from 
neurofibrils producing the initial "neurofibillary tangles" structures that 
are the major diagnostic hallmark of AD brain.

The net result of the National Institutes of Aging has been, in my opinion, 
one big collect yawn.  In my mind there is no doubt that the years of 
training amyloid based researchers has permeated the NIH and Alzheimer's 
Association to the point that individuals proposing other hypotheses are 
treated like major enemies of the realm.
  While I can still appreciate why someone would not like the mercury and 
other heavy metals are causal for AD there is no logical argument that 
would follow that mercury and other heavy metal exposures would exacerbate 
the clinical symptoms of AD.  In my opinion, exposure to mercury and other 
heavy metal toxicants is the most likely cause of AD.  The arguments that 
amyloid or oxidative stress is the cause is, in my opinion, looking at the 
results of the disease and calling them the cause.  In AD the brain cells 
are dying and any decently trained biochemist would surmise immediately 
that finding oxidative stress in a dying neuron system (i.e. AD brain) 
would be like finding rocks in a stone quarry----yet this is what our NIH 
mostly funds.  Boyd Haley
 

At 04:35 PM 4/10/04 +0100, you wrote:
>Boyd Haley mentions that when his Alzheimer/Hg findings began to be
>published, his funding precipitously decreased.
>Teresa Binstock (mercury research articles posted at the end of the below
>article)
>
>link>
>Is Alzheimer's field blocking R&D into other causes?
>
>
>By SHARON BEGLEY
>The Associated Press
>4/9/04 9:42 AM
>
>
>The Wall Street Journal
>
>Jie Shen describes the past two years of her scientific life as "torture,"
>but she can't say she wasn't warned. In the mid-1990s, as a young
>researcher in the lab of a Nobel-winning neuroscientist, she grew curious
>about alternatives to the leading hypothesis of Alzheimer's disease, and in
>virtually any other field she would have been free, even encouraged, to
>follow her scientific curiosity wherever it led. But her mentor warned her
>off. Alzheimer's, he said, is not like other fields.
>
>She found that out the hard way during an odyssey that has finally
>culminated in the publication of an eye-opening paper. In a nutshell, a
>team led by Dr. Shen, a molecular geneticist and neurobiologist at Harvard
>Medical School, Boston, shut down two mouse genes whose human forms have
>been linked to inherited forms of Alzheimer's.
>
>According to the leading theory of the disease, these so-called presenilin
>genes are involved in the production of beta-amyloid, a protein that forms
>gumball-like "plaques" in the brain. Those plaques, in turn, are widely
>thought to kill brain cells, erase synapses and memory, and lead,
>ultimately and often blessedly, to death.
>
>But adult mice missing the presenilin genes, and hence the supposedly toxic
>amyloid protein, still suffered memory problems and brain-cell death, just
>as in Alzheimer's. Dr. Shen and her colleagues concluded that amyloid is
>something the brain likely needs in order to think, remember and keep
>neurons alive, not something that gums it up, as the "amyloid hypothesis"
>holds.
>
>When the Harvard scientists submitted their findings to two leading
>journals beginning in 2002, they hit a brick wall. One peer-reviewer shot
>back with a long list of criticisms that took them months to address.
>Another demanded they figure out the molecular mechanism behind the effects
>in the mice, and then when they did that, demanded yet more detail -- the
>mechanism underlying the mechanism, as it were -- something pretty much
>unheard of for a paper of this kind.
>
>"Powerful people in this field think that amyloid causes Alzheimer's and
>won't consider research that questions the amyloid hypothesis," says one of
>the Harvard scientists. Competing theories blame other proteins (including
>those called APP and tau), toxic metals, cholesterol or inflammation for
>Alzheimer's.
>
>The Harvard team thinks it would have been nice for the world to know its
>results two years ago, not Thursday when they were finally published in the
>journal Neuron. "One day," says one of the Neuron authors, "I'll write a
>book, 'The Dark Side of Science.' "
>
>Amyloid enthusiasts deny that they have formed some kind of cabal. They
>believe that amyloid offers the best shot at defeating Alzheimer's and so
>view the pursuit of other avenues as a waste of resources. But something
>else seems to be at work.
>
>"Whenever you have a field with limited funding, and a small number of
>people with big egos who have everything invested in one idea, you have the
>right chemistry for one theory to become so pervasive nothing else can
>fluorish," says Zaven Khachaturian, who ran research at the National
>Institute of Aging from 1977 to 1995. He calls the dominance of the amyloid
>hypothesis and the strangling of alternatives "one of the most important
>issues in science today."
>
>The result of the amyloid orthodoxy is that for 20 years this one
>hypothesis has ruled Alzheimer's, dominating the research of scientists
>seeking understanding and pharmaceutical companies seeking treatments. "The
>amyloid people are very powerful, and have been dogmatic in opposing
>alternative (hypotheses)," says molecular biologist Rachael Neve of Harvard.
>
>Despite hundreds of experiments casting doubt on the neurotoxicity of
>amyloid, maverick and innovative ideas get crushed. As my colleague Bernard
>Wysocki reported in December, after Ashley Bush of Harvard broke with the
>amyloid camp, journals rejected his papers and funding agencies turned down
>his grant proposals.
>
>"It has been very difficult to get funding for anything that's not based on
>the amyloid cascade, or to publish alternatives to the amyloid hypothesis
>in top-tier journals," says Thomas Wisniewski, associate professor of
>neurology and pathology at New York University School of Medicine in New
>York City.
>
>Such dogmatism is usually a bad idea in science, and when it comes to
>Alzheimer's, the effect has been nothing short of tragic. By putting almost
>all its eggs in the amyloid basket, the Alzheimer's establishment has
>impeded progress on the disease. Because research chasing the demon amyloid
>gets the lion's share of financial support and dominates the high-profile
>journals, antiamyloid treatments receive most of the R&D support, too. Few
>other approaches to cures are in the pipeline.
>
>"I think we've lost some time," says Dr. Wisniewski. Neuropathologist
>George Perry of Case Western Reserve University, Cleveland, draws an
>analogy to the criminal-justice system. "Executing beta-amyloid," he says,
>"leaves the killer loose in the brain."
>
>Next week, I'll explore the failings of the amyloid hypothesis, and discuss
>what has befallen scientists who challenge it.
>
>
>*****
>1: Neurotoxicology. 1997;18(2):315-24.
>Mercury vapor inhalation inhibits binding of GTP to tubulin in rat brain:
>similarity to a molecular lesion in Alzheimer diseased brain.
>Pendergrass JC, Haley BE, Vimy MJ, Winfield SA, Lorscheider FL.
>College of Pharmacy, University of Kentucky, Lexington 40536, USA.
>
>Hg2+ interacts with brain tubulin and disassembles microtubules that
>maintain neurite structure. Since it is well known that Hg vapor (Hg0) is
>continuously released from "silver" amalgam tooth fillings and is absorbed
>into brain, rats were exposed to Hg0 4h/day for 0, 2, 7, 14 and 28 d at 250
>or 300 micrograms Hg/m3 air, concentrations present in mouth air of some
>humans with many amalgam
>fillings. Average rat brain Hg concentrations increased significantly
>(11-47 fold) with duration of Hg0 exposure. By 14 d Hg0 exposure,
>photoaffinity labelling on the beta-subunit of the tubulin dimer with
>[alpha 32P] 8N3 GTP in brain homogenates was decreased 41-74%, upon
>analysis of SDS-PAGE autoradiograms. The identical neurochemical lesion of
>similar or greater magnitude is evident in Alzheimer brain homogenates from
>approximately 80% of  patients, when compared to human age-matched
>neurological controls. Total tubulin protein levels remained relatively
>unchanged between Hg0 exposed rat
>brains and controls, and between Alzheimer brains and controls. Since the
>rate of tubulin polymerization is dependent upon binding of GTP to tubulin
>dimers, we conclude that chronic inhalation of low-level Hg0 can inhibit
>polymerization of brain tubulin essential for formation of microtubules.
>PMID: 9291481 [PubMed - indexed for MEDLINE]
>
>
>2: Met Ions Biol Syst.  1997;34:461-78.
>Inhibition of brain tubulin-guanosine 5'-triphosphate interactions by
mercury:
>similarity to observations in Alzheimer's diseased brain.
>Pendergrass JC, Haley BE.
>College of Pharmacy, Division of Medicinal Chemistry and Pharmaceutics,
>University of Kentucky Medical Center, Lexington 40536-0082, USA.
>Publication Types:
>     Review
>     Review, Tutorial
>PMID: 9046580 [PubMed - indexed for MEDLINE]
 
 

Boyd E. Haley  859-257-7082
Professor and Chair
Dept. of Chemistry
University of Kentucky