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Earlier Inflammation
Blamed
New Hypothesis
About Alzheimer's Disease
Note: Below this news article is a history and background on Alzheimer's
disease.
March 16, 2004 -
A new theory about Alzheimer's disease blames the cause on inflammation,
which creates abnormal metabolites out of normal brain molecules.
These abnormal metabolites then modify "amyloid
beta" proteins in the brain and cause them to misfold. Misfolded amyloid
beta proteins are thought to be a major player in Alzheimer's disease,
because they can accumulate into the fibrils and plaques that autopsies
reveal in the brains of patients with the disease. These fibrils and
plaques and their precursors are implicated in neuronal loss.
The inflammation process that creates these
metabolites can be triggered by numerous stimuli, including infections
that precede the onset of Alzheimer's disease by a significant amount of
time -- perhaps years.
This hypothesis about the cause of Alzheimer's
disease, the progressive neurodegenerative disorder that currently
afflicts some 4.5 million Americans, is proposed by scientists at
The Scripps Research Institute.
"If a certain inflammatory metabolite or family of
metabolites confers risk later in life, then we need to know this, and
we need to attack the problem," says Scripps Research Professor Jeffery
W. Kelly, who is the Lita Annenberg Hazen Professor of Chemistry in The
Skaggs Institute for Chemical Biology and vice president of academic
affairs at Scripps Research.
Kelly and his Scripps Research colleagues present
their new theory in an article that will be published in an upcoming
issue of the journal Proceedings of the National Academy of Sciences.
A Progressive,
Incurable Disease
(The following information on
Alzheimer's and its history was provided by The Scripps Research
Institute)
Alzheimer's is a progressive neurodegenerative
disease marked by memory loss, loss of language ability, loss of the
ability to mentally manipulate visual information, poor judgment,
confusion, restlessness, and mood swings. According to the Alzheimer's
Disease Education and Referral Center, a service of the National
Institute on Aging, Alzheimer's disease is now believed to inflict some
4.5 million people and is the most common form of dementia among older
people in the United States. Currently, there is no cure for Alzheimer's
and no way to slow the progression of the disease.
German doctor Alois Alzheimer discovered the
disease in 1906, when he examined a post-mortem patient who had died
with an unusual mental illness. Alzheimer found unusual clumps of
protein or plaques in her brain. These plaquesmade up of aggregated
proteins called amyloid betaare a clear sign of the disease, and the
aggregation of amyloid beta protein is an accepted primary pathological
marker for Alzheimer's.
But scientists have not been sure whether these
fibrils are causing the disease or are simply a marker of it. By
analogy, a tidal wave may cause massive destruction to a coastal area,
but the tidal wave itself may have been caused by a distant earthquake
undetected in that coastal area.
Kelly and his colleagues have studied the basic
biology of Alzheimer's and related diseases for many years, looking for
new treatment approaches. Now, they think they may have taken a
significant step along this path by identifying the distant earthquake
that causes Alzheimer's.
Basic Science Brings it All Together
Amyloid diseases are caused by the misfolding of
proteins into structures that lead them to cluster together, forming
microscopic fibril or plaques, which deposit in internal organs and
interfere with normal function, sometimes lethally. In the case of
Alzheimer's, these fibrils kill nerve cells in areas of the brain that
are crucial for memory.
These diseases include Alzheimer's, Parkinson's,
and a peripheral nervous system disease called familial amyloid
polyneuropathy (FAP)a collection of more than 80 rare amyloid diseases
caused by the misfolding of the protein transthyretin (TTR), which the
liver secretes into the bloodstream to carry thyroid hormone and vitamin
A.
In the FAP diseases, mutations in the TTR protein
are known to play a direct role in causing the disease. Basically, these
mutations change the amino acid sequence of TTR, and these changes alter
protein folding in such a way as to predispose the proteins to misfold
and accumulate into microscopic fibrils, which can then grow into the
protein plaques characteristic of FAP and other amyloid diseases.
However, in Alzheimer's disease, the cause of
misfolding is not so obvious. A number of mutations are associated with
rare forms of familial Alzheimer's, but not with most common cases
(about 95 percent of the cases). This suggests there must be a more
common cause of Alzheimer's disease, and Kelly has combined efforts with
several of his colleagues at Scripps Research to find it.
A few years ago, Kelly started to think about
traumatic head injuries, which are a major risk factor for later
developing Alzheimer's disease. The body responds to such injuries with
inflammatory reactions that cause the release of components of lipid
membranes, such as cholesterol.
Kelly began to discuss this with his colleagues in
The Skaggs Institute for Chemical Biology, Scripps Research President
Richard A. Lerner, M.D., and Scripps Research Associate Professor Paul
Wentworth, Jr., Ph.D. Lerner and Wentworth had recently discovered how
inflammation can lead to the production of reactive oxygen species such
as ozone, which can trigger pathological changes in other molecules in
the body, like cholesterol.
In a paper last year, Lerner, Wentworth, and
several colleagues described how ozone reacts with normal metabolites to
produce toxic compounds during inflammatory processes taking place in
the body. The scientists describe two such compounds, which they call
the "atheronals." The scientists suggest these newly identified products
are critical to the pathogenesis of the disease atherosclerosis because
these atheronals were found in atherosclerotic plaques that were
surgically removed from patients with atherosclerosis. (Atherosclerosis
is a common vascular disease that increases the risk of heart attacks
and strokes and is characterized by a hardening of the arteries over
time due to deposits of fibrous tissue, calcium, fat, cholesterol,
proteins, cells, and other materials on the inner "endothelial" walls of
an artery).
This discovery made Kelly sit up straight when he
first heard it because inflammation is increasingly seen as playing a
role in neurodegenerative diseases. Also, there are a fair number of
risk factors in common between the two diseases, including
hypercholesterolemia and inflammation.
In their new study, Kelly and his colleagues
suggest that inflammation in the brain could create a perfect storm in
which cholesterol and lipids react with ozone and other inflammatory
chemicals to produce abnormal reactive metabolites, which, in turn,
modify the folding of normal amyloid beta protein. These modified
amyloid beta proteins can catalyze misfolding in other unmodified
amyloid beta proteins, starting an avalanche of misfolding that results
-- perhaps years or decades later -- in Alzheimer's disease.
A New Way of Thinking About Disease in General
To examine the hypothesis that these metabolites
may be the root cause of Alzheimer's, Kelly and his colleagues examined
the post-mortem brains of Alzheimer's patients and compared these to
age-matched controls.
They found evidence of atheronals in the brains of
both the Alzheimer's patients and the control subjects. The levels of
atheronals in the brains of the Alzheimer's patients were not
significantly elevated, but this is not necessarily surprising.
According to the new theory, the propagation of misfolding and the
buildup of fibrils inside the brain does not depend upon continuous
exposure to metabolite-modified proteins, but to exposure during a
precipitating event that may occur a decade or more earlier. The
creation of these metabolite-linked misfolding proteins is only the
initiator of the fibril plaques.
Kelly and colleagues also performed experiments in
the test tube and found that atheronals and lipid oxidation products
have the ability to dramatically accelerate the misfolding of amyloid
beta and to reduce the concentration of the protein needed for
misfolding to take place to concentrations found in the brain.
This is an entirely new way of thinking about not
only Alzheimer's disease, but disease in general. Historically, science
has regarded disease as based on the up or down regulation of gene
expression or protein function. But this theory suggests a new sort of
pathology -- the creation of a reactive metabolite by inflammatory
stress, leading to the modification of a protein, the aggregation of
that protein over time, and the degeneration of function in the brain or
whichever internal organ hosts the aggregation.
The inflammatory metabolite theory of Alzheimer's
will be difficult to prove, admits Kelly, because the presence of these
abnormal metabolites are hard to detect years after they initiated the
aggregation. There is, so far, no smoking gun.
"Is [this theory] right? Time will tell," says
Kelly. "That's how science works."
The article, "Metabolite-initiated protein
misfolding may trigger Alzheimer's disease" was authored by Qinghai
Zhang, Evan T. Powers, Jorge Nieva, Mary E. Huff, Maria A. Dendle, Jan
Bieschke, Charles G. Glabe, Albert Eschenmoser, Paul Wentworth, Jr.,
Richard A. Lerner, and Jeffery W. Kelly and appears in the online
edition of the journal Proceedings of the National Academy of Sciences
the week of March 15-19, 2004. The article will appear in print later
this year. See: pnas.org/cgi/doi/10.1073/pnas.0400924101.
This work was supported by The Skaggs Institute for
Chemical Biology and the Lita Annenberg Hazen Foundation.
About The Scripps Research Institute
The Scripps Research Institute in La Jolla,
California, is one of the world's largest, private, non-profit
biomedical research organizations. It stands at the forefront of basic
biomedical science that seeks to comprehend the most fundamental
processes of life. Scripps Research is internationally recognized for
its research into immunology, molecular and cellular biology, chemistry,
neurosciences, autoimmune diseases, cardiovascular diseases and
synthetic vaccine development.
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