Imaging study reveals rapid formation
of Alzheimer's-associated plaques
Animal study shows new plaques
develop in 24 hours, neuronal changes soon after
BOSTON - February 6, 2008 - The amyloid plaques found in
the brains of Alzheimer's disease patients may form much more rapidly
than previously expected. Using an advanced microscopic imaging
technique to examine brain tissue in mouse models of the devastating
neurological disorder, researchers from the MassGeneral
Institute for Neurodegenerative Disease (MGH-MIND), working
with colleagues from Washington University School of Medicine, find
that plaques can develop in as little as a day and that Alzheimer's-associated
neuronal changes appear soon afterwards. Their report will appear
in the Feb. 7 issue of Nature.
"While we've known for a long time what amyloid plaques and
other changes seen in the brains of Alzheimer's patients look like,
we didn't know in what order and at what speed those changes occur,"
says Bradley Hyman, MD, PhD, director of the Alzheimer's
Unit at MGH-MIND and senior author of the Nature paper.
"Understanding the rules that govern plaque formation may lead
us to ideas about how to intervene in the process."
To investigate the timing of these brain changes, the researchers
used a novel technique for microscopically imaging the brains of
living animals. Using several strains of transgenic mice destined
to develop amyloid plaques, they imaged initially plaque-free areas
of the brain on a regular basis - first weekly and, in subsequent
experiments, daily. Although plaques formed rarely, they could appear
as little as 24 hours after a previous plaque-free image was taken.
The new plaques were similar in appearance to those seen in the
brains of Alzheimer's patients and in the mouse models, and subsequent
imaging showed little change in the size of plaques once they had
Earlier investigations have shown that levels of microglia - neuronal
support cells that react to inflammation and other damage - rise
in the vicinity of amyloid plaques. Imaging an Alzheimer's mouse
model that expresses a fluorescent marker in microglia showed that
the cells were attracted to new plaques within a day of formation.
Although there was no evidence that microglia were actively removing
the plaques, the investigators hypothesize that they may help restrict
further plaque growth. Examining neurons adjacent to plaques showed
that the kind of changes associated with Alzheimer's - distortions
in the projections through which neuronal signals pass - appear
rapidly and approach maximum effect within five days.
"These results confirm the suspicion we've had that plaques
are a primary event in the glial and neuronal changes that underlie
Alzheimer's dementia," Hyman says. "We hope that what
we've learned about the time frame and sequence of events will help
us find ways to keep plaques from forming." Hyman is the John
Penny Professor of Neurology at Harvard Medical School.
Melanie Meyer-Luehmann, PhD, of MGH-MIND is the first author of
the Nature report; Washington University School of Medicine
co-authors Jessica Koenigsknecht-Talboo, PhD, and David Holtzman,
MD, provided the transgenic mice and collaborated on the microglial
experients. Aditional co-authors are Tara Spires-Jones, Claudia
Prada, MD, Monica Garcia-Alloza, Alix de Calignon, Anete Rozkalne,
and Brian Bacskai, PhD, all of MGH-MIND. The study was supported
by grants from the National Institutes of Health and the Alzheimer's
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of more than $500 million
and major research centers in AIDS, cardiovascular research, cancer,
computational and integrative biology, cutaneous biology, human
genetics, medical imaging, neurodegenerative disorders, regenerative
medicine, systems biology, transplantation biology and photomedicine.
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