Scientists Isolate a Toxic Key to Alzheimer's
Disease in Human Brains
Soluble Beta-Amyloid Protein Fragments May Damage Brain Cells,
Scientists have long questioned whether the abundant amounts of
amyloid plaques found in the brains of patients with Alzheimer's
actually caused the neurological disease or were a by-product of
its progress. Now, using new research techniques, scientists have
shown that a two-molecule aggregate (or dimer) of beta-amyloid
protein fragments may play a role in initiating the disease. The
study, supported by the National Institutes of Health, suggests
a possible new target for developing drug therapies to combat the
irreversible and progressive disorder.
Ganesh M. Shankar, Ph.D., and Dennis J. Selkoe, M.D., of Brigham
and Women's Hospital and Harvard Medical School, conducted the
study in collaboration with other researchers at Harvard and in
Ireland at University College Dublin, Beaumont Hospital and Royal
College of Surgeons Ireland, and Trinity College Dublin. The National
Institute on Aging (NIA), part of NIH, funded the study which appears
online in the June 22, 2008, Nature Medicine.
Alzheimer's disease is marked by the build-up of plaques consisting
of beta-amyloid protein fragments, as well as abnormal tangles
of tau protein found inside brain cells. Early in the disease,
Alzheimer's pathology is first observed in the hippocampus, the
part of the brain important to memory, and gradually spreads to
the cerebral cortex, the outer layer of the brain. In this study,
researchers tested cerebral cortex extracts from brains donated
for autopsy by people aged 65 and older with Alzheimer's and other
dementias, as well as those without dementia. The extracts contained
soluble one-molecule (monomer), two-molecule (dimer), three-molecule
(trimer) or larger aggregates of beta-amyloid, as well as insoluble
plaque cores. The researchers then injected the extracts into normal
rats or added the extracts to slices of normal mouse hippocampus.
Shankar, Selkoe and colleagues discovered that both the soluble
monomers and the insoluble plaque cores had no detectable effect
on the hyppocampal slices. However, the soluble dimers induced
certain key characteristics of Alzheimer's in the rats. The dimers
impaired memory function, specifically the memories of newly learned
behaviors. In the mouse hippocampal slices, the dimers also reduced
by 47 percent the density of the dendrite spines that receive messages
sent by other brain cells. The dimers seemed to be directly acting
on synapses, the connections between neurons that are essential
for communication between them.
To confirm this effect, the researchers then injected certain
antibodies against beta-amyloid protein fragments. These latched
onto and inactivated the dimers, preventing their toxic effects
in the animal models. However, much work remains to be done before
inactivation of dimers could move into the clinic.
"Scientists have theorized for many years that soluble beta-amyloid
may be critical to the development and progression of this devastating
disease. Now these researchers have isolated a candidate causative
agent from brains of people with typical Alzheimer's and directly
tested it in an animal model," said NIA Director Richard J.
Hodes, M.D. "While more research is needed to replicate and
extend these findings, this study has put yet one more piece into
place in the puzzle that is Alzheimer's."
The animal findings were consistent with what the researchers
found when they examined the brain tissues of people who had been
clinically diagnosed with Alzheimer's and those without dementia.
They detected soluble dimers and some trimers of amyloid in the
brains of patients with Alzheimer's, but none or very low levels
in those free of the disorder. Some people free of the disorder,
however, did have insoluble amyloid plaques in their brains.
"These findings may help explain why people with normal cognitive
function are sometimes found to have large amounts of amyloid plaques
in their brains, which has been a puzzle for some time," said
Marcelle Morrison-Bogorad, Ph.D., director of the NIA Division
of Neuroscience. "Their findings noted that the brain of an
individual who was never clinically diagnosed with dementia was
found with abundant insoluble Alzheimer's plaques, but no soluble
Selkoe and Shankar noted that further insights into the early
stages of this disease process may answer questions not only about
Alzheimer's, but also about age-related memory impairments. "The
approaches we used to isolate dimers and the widespread availability
of tissues from brain banks, open new avenues of investigation
into how these aggregates induce Alzheimer's disease," said
Selkoe. "We still need to find out why dimers in particular
are so destructive to neurons."
NIA leads the federal government effort conducting and supporting
research on the biomedical and social and behavioral aspects of
aging and the problems of older people. For more information on
aging-related research and the NIA, please visit www.nia.nih.gov.
The NIA provides information on age-related cognitive change and
neurodegenerative disease specifically at its Alzheimer's Disease
Education and Referral (ADEAR) Center site at www.nia.nih.gov/Alzheimers.
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please visit either Web site.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and Centers
and is a component of the U.S. Department of Health and Human Services.
It is the primary federal agency for conducting and supporting basic,
clinical and translational medical research, and it investigates
the causes, treatments, and cures for both common and rare diseases.
For more information about NIH and its programs, visit www.nih.gov.