Contact: Karen Teber
Georgetown University Medical Center
Tau, not amyloid-beta, triggers neuronal death process in
WASHINGTON — New research points to tau, not amyloid-beta (Abeta)
plaque, as the seminal event that spurs neuron death in disorders
such as Alzheimer’s disease. The finding, which dramatically alters
the prevailing theory of Alzheimer’s development, also explains why
some people with plaque build-up in their brains don’t have
The study is published online today in the journal Molecular
Neuronal death happens when tau, found inside neurons, fails to
function. Tau’s role is to provide a structure — like a train track
—inside brain neurons that allows the cells to clear accumulation
of unwanted and toxic proteins.
“When tau is abnormal, these proteins, which include Abeta,
accumulate inside the neurons,” explains the study’s senior
investigator, Charbel E-H Moussa, MB, PhD, assistant professor of
neuroscience at Georgetown University Medical Center. “The cells
start to spit the proteins out, as best they can, into the
extracellular space so that they cannot exert their toxic effects
inside the cell. Because Abeta is ‘sticky,’ it clumps together into
plaque,” Moussa says.
He says his study suggests the remaining Abeta inside the neuron
(that isn’t pushed out) destroys the cells, not the plaques that
build up outside. “When tau does not function, the cell cannot
remove the garbage, which at that point includes Abeta as well as
tangles of nonfunctioning tau, and the cell dies. The Abeta
released from the dead neuron then sticks to the plaque that had
Moussa’s experiments in animal models also show less plaques
accumulate outside the cell when tau is functioning; when tau was
reintroduced into neurons that did not have it, plaques did not
Malfunctioning tau can occur due to errant genes or through aging.
As individuals grow older, some tau can malfunction while enough
normal tau remains to help clear the garbage. In these cases, the
neurons don’t die, he says. “That explains the confusing clinical
observations of older people who have plaque build-up, but no
dementia,” Moussa says.
Moussa has long sought a way to force neurons to clean up their
garbage. In this study, he shows that nilotinib, a drug approved to
treat cancer, can aid in that process. Nilotinib helps the neuron
clear garbage, but requires some functional tau, he says.
“This drug can work if there is a higher percentage of good to bad
tau in the cell,” Moussa says. “There are many diseases of dementia
that have malfunctioning tau and no plaque accumulation, such as
frontal temporal dementia linked to Parkinsonism,” Moussa says.
“The common culprit is tau, so a drug that helps tau do its job may
help protect against progression of these diseases.”
Co-authors include researchers from Capital Medical University in
Beijing, China, and Merck Research Laboratories.
Funding for these studies was provided by Georgetown University
grants and by Merck & Co.
Moussa is an inventor on a Georgetown University patent application
for use of nilotinib as a therapeutic approach in neurodegenerative
About Georgetown University Medical Center
Georgetown University Medical Center (GUMC) is an internationally
recognized academic medical center with a three-part mission of
research, teaching and patient care (through MedStar Health).
GUMC’s mission is carried out with a strong emphasis on public
service and a dedication to the Catholic, Jesuit principle of cura
personalis — or “care of the whole person.” The Medical Center
includes the School of Medicine and the School of Nursing & Health
Studies, both nationally ranked; Georgetown Lombardi Comprehensive
Cancer Center, designated as a comprehensive cancer center by the
National Cancer Institute; and the Biomedical Graduate Research
Organization, which accounts for the majority of externally funded
research at GUMC including a Clinical and Translational Science
Award from the National Institutes of Health.
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