Toxic protein could explain Alzheimer's and lead to breakthroughs
August 20, 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.
Northwestern University
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