ALZHEIMER'S DISEASE PATHWAY REVEALED BY RESEARCH
Researchers at
Jacksonville's campus of Mayo Clinic have discovered a defect in a key
cell-signaling pathway they say contributes to both overproduction of toxic
protein in the brains of Alzheimer's disease patients as well as loss of
communication between neurons -- both significant contributors to this type of
dementia
Their study, in the
online issue of Neuron, offers the potential that targeting this
specific defect with drugs "may rejuvenate or rescue this pathway,"
says the study's lead investigator, Guojun Bu, Ph.D., a neuroscientist at Mayo
Clinic, Jacksonville, Fla.
"This defect is
likely not the sole contributor to development of Alzheimer's disease, but our
findings suggest it is very important, and could be therapeutically targeted to
possibly prevent Alzheimer's or treat early disease," he says.
The pathway, Wnt
signaling, is known to play a critical role in cell survival, embryonic
development and synaptic activity -- the electrical and chemical signals
necessary for learning and memory. Any imbalance in this pathway (too much or
too little activity) leads to disease -- the overgrowth of cells in cancer is
one example of overactivation of this pathway.
While much research on
Wnt has focused on diseases involved in overactive Wnt signaling, Dr. Bu's team
is one of the first to demonstrate the link between suppressed Wnt signaling
and Alzheimer's disease.
"Our finding
makes sense, because researchers have long known that patients with cancer are
at reduced risk of developing Alzheimer's disease, and vice versa," Dr. Bu
says. "What wasn't known is that Wnt signaling was involved in that dichotomy."
Using a new mouse
model, the investigators discovered the key defect that leads to suppressed Wnt
signaling in Alzheimer's. They found that the low-density lipoprotein
receptor-related protein 6 (LRP6) is deficient, and that LRP6 regulates both
production of amyloid beta, the protein that builds up in the brains of AD
patients, and communication between neurons. That means lower than normal
levels of LRP6 leads to a toxic buildup of amyloid and impairs the ability of
neurons to talk to each other.
Mice without LRP6 had
impaired Wnt signaling, cognitive impairment, neuroinflammation and excess
amyloid.
The researchers
validated their findings by examining postmortem brain tissue from Alzheimer's
patients -- they found that LRP6 levels were deficient and Wnt signaling was
severely compromised in the human brain they examined.
The good news is that
specific inhibitors of this pathway are already being tested for cancer
treatment. "Of course, we don't want to inhibit Wnt in people with
Alzheimer's or at risk for the disease, but it may be possible to use the
science invested in inhibiting Wnt to figure out how to boost activity in the
pathway," Dr. Bu says.
"Identifying
small molecule compounds to restore LRP6 and the Wnt pathway, without inducing
side effects, may help prevent or treat Alzheimer's disease," he says.
"This is a really exciting new strategy -- a new and fresh approach."
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