Soluble Beta-Amyloid Protein Fragments May Damage Brain Cells, Study Finds

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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 certain 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 hippocampal 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 beta-amyloid."
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."