Broken Switch in Aging Brain May Cause the Darkness
of Alzheimer’s
Paradoxical Alzheimer's finding may shed new light
on memory loss
March 13, 2008 – Do you remember the seventh song
that played on your radio on the way to work yesterday? Most of people
don’t, even if they are not senior citizens, 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, 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.
Editor’s Notes:
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.
