August 19, 2003
Protein
May Be Factor in Alzheimer’s Disease
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 are published online
by the Proceedings of the National Academy of Sciences.
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 _-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's Feinberg
School of Medicine 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. |