Neurons in the brain are connected to many
other neurons through long processes called
axons. Their functions depend on the
transport of diverse cargoes up and down
these important pipelines. Particularly
important among the cargoes are
mitochondria, the energy factories of the
cell, and proteins that support cell growth
and survival. Aβ proteins, which build up to
toxic levels in the brains of people with
AD, impair the axonal transport of these
cargoes.
"We previously showed that suppressing the
protein tau can prevent Aβ from causing
memory deficits and other abnormalities in
mouse models of AD," explained Lennart Mucke,
MD, GIND director and senior author of the
study.
"We wondered whether this striking rescue might
be caused, at least in part, by improvements
in axonal transport."
The scientists explored this possibility in
mouse neurons grown in culture dishes.
Neurons from normal mice or from mice
lacking one or both tau genes were exposed
to human Aβ proteins.
The Aβ slowed down axonal transport of
mitochondria and growth factor receptors,
but only in neurons that produced tau and
not in neurons that lacked tau. In the
absence of the Aβ challenge, tau reduction
had no effect on axonal transport.
"We are really excited about these results,"
said Keith Vossel, MD, lead author of the
study. "Whether tau affects axonal transport
or not has been a controversial issue, and
nobody knew how to prevent Aβ from impairing
this important function of neurons. Our
study shows that tau reduction accomplishes
this feat very effectively."
"Some treatments based on attacking Aβ have
recently failed in clinical trials, and so,
it is important to develop new strategies
that could make the brain more resistant to
Aβ and other AD-causing factors," said Dr.
Mucke.
"Tau reduction looks promising in this regard,
although a lot more work needs to be done
before such approaches can be explored in
humans."
The team also included Gladstone's Jens
Brodbeck, Aaron Daub, Punita Sharma, and
Steven Finkbeiner. Kai Zhang and Bianxiao
Cui of Stanford's chemistry department also
contributed to the research.
The NIH and the McBean Family Foundation
supported this work.
Lennart Mucke's primary affiliation is with the
Gladstone Institute of Neurological Disease,
where he is Director/Senior Investigator and
where his laboratory is located and his
research is conducted. He is also the Joseph
B. Martin Distinguished Professor of
Neuroscience at UCSF.
The Gladstone Institutes is a nonprofit,
independent research and educational
institution, consisting of the Gladstone
Institute of Cardiovascular Disease, the
Gladstone Institute of Virology and
Immunology, and the Gladstone Institute of
Neurological Disease. Independent in its
governance, finances and research programs,
Gladstone shares a close affiliation with
UCSF through its faculty, who hold joint
UCSF appointments.
