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Toxic
Protein Could Explain Alzheimer's and Lead to Breakthroughs
By Megan Fellman, Eurekalert August 19, 2003
EVANSTON, Ill. -- Researchers at Northwestern University have discovered for the first time in humans the presence of a toxic protein that they believe to be responsible for the devastating memory loss found in individuals suffering from Alzheimer's disease. An understanding of
this key molecular link in the progression of Alzheimer's could lead to
the development of new therapeutic drugs capable of reversing memory loss
in patients who are treated early, in addition to preventing or delaying
the disease. Help for individuals with pre-Alzheimer's memory failure
(mild cognitive impairment) also is envisioned. The findings will be
published online by the Proceedings of the National Academy of Sciences
during the week of Aug. 18. The research team,
led by William L. Klein, professor of neurobiology and physiology, found
up to 70 times more small, soluble aggregated proteins called "amyloid
b-derived diffusible ligands" (ADDLs, pronounced "addles")
in the brain tissue of individuals with Alzheimer's disease compared to
that of normal individuals. The clinical data
strongly support a recent theory in which ADDLs accumulate at the
beginning of Alzheimer's disease and block memory function by a process
predicted to be reversible. ADDLs have the ability to attack the
memory-building activity of synapses, points of communication where
neurons exchange information, without killing neurons. "Researchers for
more than a decade thought it was big molecules, the 'amyloid fibrils,'
that caused memory problems, but we think the real culprits are extremely
small molecules, what we call ADDLs," said Klein, who is a member of
Northwestern's Cognitive Neurology and Alzheimer's Disease Center.
"Now we've shown that ADDLs are present in humans and are a
clinically valid part of Alzheimer's pathology. If we can develop drugs
that target and neutralize these neurotoxins, it might be possible to not
only slow down memory loss, but to actually reverse it, to bring memory
function back to normal." Although both are a
form of amyloid beta, ADDLs and their properties differ significantly from
the amyloid fibrils (known as plaques) that are a diagnostic hallmark of
Alzheimer's. ADDLs found in human brains, mostly 12 or 24 amyloid beta
proteins clumped together, are tiny and undetectable in conventional
neuropathology; fibrils are much, much larger. While fibrils are immobile
toxic waste dumps, ADDLs are soluble and diffuse between brain cells until
they find vulnerable synapses. (Single pieces of amyloid beta protein in
the brain is normal.) "The difference
between ADDLs and fibrils is like comparing four eggs, over easy, to an
enormous omelet that could feed the entire Chicago Bears team," said
Klein. ""You start with eggs, but the final product taste,
texture and size are all different." The existence of
ADDLs may help explain the poor correlation between plaques and
neurological deficits. Studies by other researchers have shown a reversal
of memory failure in mouse models treated with amyloid beta antibodies --
but without any reduction in plaque. The antibodies appear to restore
memory because they neutralize ADDLs, which Klein's group has found in
mouse models with Alzheimer's as well as in human brains with Alzheimer's.
Klein's research team
recently began a study funded by the National Institutes of Health to
continue investigating ADDLs in humans and further characterize these
molecules. In addition to Alzheimer's disease, ADDL-like molecules could
be the cause of other degenerative diseases. Klein also is working
with researchers at Northwestern's Institute for Nanotechnology on
clinical diagnostics capable of detecting ADDLs in blood or cerebral
spinal fluid. Currently diagnosis of Alzheimer's is based primarily on a
battery of psychological tests. "Now that ADDLs
have been discovered in humans we would like to develop effective
diagnostics and that means employing nanotechnology," said Klein.
"That's because ADDLs are present in very low concentrations, and
nanotechnology has the potential to provide the ultra-sensitive assays
needed for the clinic." Klein, Grant A.
Krafft, formerly at Northwestern University Medical School and now chief
scientific officer at Acumen Pharmaceuticals, Inc., and Caleb E. Finch,
professor of biological sciences and gerontology at the University of
Southern California, reported the discovery of ADDLs in 1998. Krafft and
Finch are co-authors on the PNAS paper. Northwestern and USC hold joint
patents on the composition and use of ADDLs in neurodisorders. The patent rights
have been licensed to Acumen Pharmaceuticals, based in Glenview, Ill., for
the development of drugs that treat Alzheimer's disease and other
memory-related disorders. Clinical trials could be two or three years
away. In addition to Klein,
Krafft and Finch, other authors on the paper are Yuesong Gong (lead
author), Lei Chang, Kirsten L. Viola, Pascale N. Lacor and Mary P.
Lambert, from Northwestern University. The research was
supported by the National Institutes of Health, the Boothroyd, Feiger and
French foundations, and the Institute for the Study of Aging. Copyright
© 2002 Global Action on Aging
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