By the time most
people receive a diagnosis of Alzheimer’s disease — based on clinical signs of
mental decline — their brains have already suffered a decade or more of damage.
But although the mechanisms that spur the destruction of neurons in Alzheimer’s
disease are not yet fully understood, two well-documented signs of the condition
are accumulation of the amyloid-β peptide (the main component of plaques found
in Alzheimer’s patient brains) and chronic inflammation.
New research from
Rockefeller University, published March 16 in the Proceedings of the National
Academy of Sciences, identifies a bridge between the two. That bridge, a
molecular cascade known as the contact system, may provide opportunities for
early diagnosis of the disease through simple blood tests.
“People have been
looking for a long time for markers for Alzheimer’s disease,” says Sidney
Strickland, head of the Patricia and John Rosenwald Laboratory of Neurobiology
and Genetics. But current diagnostic tests for pre-symptomatic Alzheimer’s
leave much to be desired. Evaluating the level of amyloid-β in the cerebral
spinal fluid, for instance, requires an invasive spinal tap procedure.
“Finding a blood
biomarker that would let us know through a simple test whether someone is on
their way to developing the disease would be a significant advance,” says first
author Daria Zamolodchikov, a postdoctoral associate in the Strickland lab.
The new study grew
from the lab’s ongoing work that looks at how the vascular system is involved
in Alzheimer’s disease. It has been shown that amyloid-β can activate a protein
in plasma called factor XII, the first step in a pathway known as the contact
system. When activated, this system leads to the release of a small peptide
called bradykinin, a molecule known to promote potentially damaging
inflammation. Although some studies have found these molecules in the cerebral
spinal fluid and brain tissue of Alzheimer’s patients, no one had studied them
in Alzheimer’s patient plasma.
Using plasma from
people with and without diagnosed Alzheimer’s disease, the researchers measured
the activation levels of the contact system. They found increased activation of
this system in the plasma of Alzheimer’s patients, potentially implicating it
in the inflammatory pathology of the disease. Moreover, in a subset of patients
whose amyloid-β levels in the cerebral spinal fluid were known, the researchers
demonstrated a positive correlation between activation of the contact system
and changes in cerebral spinal fluid amyloid-β levels, which as mentioned above
are correlated with the development of Alzheimer’s.
The researchers found
similar activation of the contact system in mouse models of Alzheimer’s, which
are genetically modified to overproduce amyloid-β. They then conducted a
follow-up experiment with healthy mice. “We went one step further and took
completely normal wild-type mice and injected them with amyloid-β. We found
that on its own, injection with amyloid-β can activate this system. It’s a
proof of principle in a complex environment,” says Zamolodchikov.
These findings will
need to be supported by studies in larger patient populations and longitudinal
studies, but they could eventually open the door to diagnosis of
pre-symptomatic Alzheimer’s based on blood levels of these molecules.
The contact system may
also offer a new approach to therapies for Alzheimer’s disease, since
inhibition of the pathway could blunt some of the inflammatory aspects of the
disease. One concern is that the contact system is also involved in blood
clotting and inhibition might carry a risk of bleeding. However, people with a
defect in this system do not have hemophilia. Thus, inhibition of this pathway
might slow progression of the disease without increasing the risk of
hemorrhage.
Fonte: http://bioengineer.org/early-diagnosis-opportunities-for-alzheimers-through-simple-blood-test/
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