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Paradoxical
Alzheimer's finding may shed new light on
Memory Loss
Newswise — Do you remember the seventh song
that played on your radio on the way to work
yesterday?
Most of us don’t, thanks to a normal
forgetting process that is constantly
“cleaning house” – culling inconsequential
information from our brains.
Researchers at the Buck Institute now
believe that this normal memory loss is
hyper-activated in Alzheimer’s disease (AD)
and that this effect is key to the profound
memory loss associated with the incurable
neurodegenerative disorder.
Last year, this same group of researchers
found that they could completely prevent
Alzheimer’s disease in mice genetically
engineered with a human Alzheimer’s
gene—“Mouzheimer’s”—by blocking a single
site of cleavage of one molecule, called APP
for amyloid precursor protein. Normally,
this site on APP is attacked by molecular
scissors called caspases, but blocking that
process prevented the disease.
Now they have studied human brain tissue and
found that, just as expected, patients
suffering from AD clearly show more of this
cleavage process than people of the same age
who do not have the disease.
However, when they extended their studies to
much younger people without Alzheimer’s
disease, they were astonished to find an
apparent paradox: these younger people
displayed as much as ten times the amount of
the same cleavage event as the AD patients.
The researchers now believe they know why.
The Buck Institute study implicates a
biochemical “switch” associated with that
cleavage of APP, causing AD brains to become
stuck in the process of breaking memories,
and points to AD as a syndrome affecting the
plasticity or malleability of the brain.
The study, due to be published in the March
7 issue of the Journal of Alzheimer’s
Disease, provides new insight into a
molecular event resulting in decreased brain
plasticity, a central feature of AD.
“Young brains operate like Ferraris –
shifting between forward and reverse, making
and breaking memories with a facility that
surpasses that of older brains, which are
less plastic,” said Dale Bredesen, MD, Buck
Institute faculty member and leader of the
research group.
“We believe that in aging brains, AD occurs
when the ‘molecular shifting switch’ gets
stuck in the reverse position, throwing the
balance of making and breaking memories
seriously off kilter.”
In previous research, lead author Veronica
Galvan, PhD, prevented this cleavage in mice
genetically engineered to develop the
amyloid plaques and deposits associated with
AD.
These surprising mice had normal memories
and showed no signs of brain shrinkage or
nerve cell damage, despite the fact that
their brains were loaded with the sticky
A-beta plaques that are otherwise associated
with Alzheimer’s disease.
“A-beta is produced throughout the brain
throughout life; we believe that it is a
normal regulator of the synapses, the
connections between neurons,” said Galvan,
who added that AD, like cancer, is a disease
in which imbalanced cell signaling plays an
important role.
“The fact that many people develop A-beta
plaques yet show no symptoms of AD tells us
that the downstream signaling of A-beta—not
just A-beta itself—is critical,” said
Bredesen, “and these pathways can be
targeted therapeutically.
Simply put, we can restore the balance.”
Continuing research at the Buck Institute
focuses on nerve signaling and efforts to
“disconnect” the molecular mechanism that
throws memory-making in the reverse
direction, as well as understanding
mechanisms that support brain cell
connections that are crucial to the process
of memory making.
AD is an incurable neurodegenerative disease
currently affecting 5.1 million Americans.
AD results in dementia and memory loss,
seriously affecting a person’s ability to
carry out activities of daily living. AD
costs the U.S. $148 billion annually, in
addition to untold family suffering.
Joining Bredesen and Galvan as co-authors of
the paper, “C-terminal cleavage of the
amyloid precursor protein at Asp664: a
switch associated with Alzheimer’s disease”
are Surita Banwait, BA; Junli Zhang, MD;
Olivia F. Gorostiza, Marina Ataie, BS; Wei
Huang, BS; and Danielle Crippen, BA of the
Buck Institute, as well as Edward H. Koo,
MD, of the University of California, San
Diego, Department of Neuroscience.
The work was supported by the Joseph Drown
Foundation, The National Institute on Aging,
the Bechtel Foundation, and the Alzheimer’s
Association.
The Buck Institute is the only freestanding
institute in the United States that is
devoted solely to basic research on aging
and age-associated disease.
The Institute is an independent nonprofit
organization dedicated to extending the
healthspan, the healthy years of each
individual’s life. The National Institute of
Aging designated the Buck a “Nathan Shock
Center of Excellence in the Biology of
Aging,” one of just five centers in the
country.
Buck
Institute scientists work in an innovative,
interdisciplinary setting to understand the
mechanisms of aging and to discover new ways
of detecting, preventing and treating
conditions such as Alzheimer’s and
Parkinson’s disease, cancer and stroke.
Collaborative research at the Institute is
supported by new developments in genomics,
proteomics and bioinformatics technology.
For more information: www.buckinstitute.org.
The Journal of Alzheimer's Disease (http://www.j-alz.com)
is an international multidisciplinary
journal to facilitate progress in
understanding the etiology, pathogenesis,
epidemiology, genetics, behavior, treatment
and psychology of Alzheimer's disease.
The journal publishes research reports,
reviews, short communications, book reviews,
and letters-to-the-editor. Groundbreaking
research that has appeared in the journal
includes novel therapeutic targets,
mechanisms of disease and clinical trial
outcomes.
The Journal of Alzheimer's Disease has an
Impact Factor of 3.058 according to Thomson
Scientific Institute for Scientific
Information's 2006 Journal Citation Reports.
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