Fla. — 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.
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, a neuroscientist at Mayo Clinic,
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.
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.
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
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."
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.
without LRP6 had impaired Wnt signaling, cognitive impairment,
neuroinflammation and excess amyloid.
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.
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.
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."
from the University of Kentucky, Xiamen University in China,
the University of Oklahoma and the Korea Brain Research
Institute participated in the study.