BUFFALO, N.Y. — Scientists have known for some time that a
protein called presenilin plays a role in Alzheimer’s
disease, and a new study reveals one intriguing way this
It has to do with how materials travel up and down brain cells,
which are also called neurons.
In an Oct.
8 paper in Human Molecular Genetics, University at Buffalo
researchers report that presenilin works with an enzyme called
GSK-3ß to control how fast materials — like proteins
needed for cell survival — move through the cells.
“If you have too much presenilin or too little, it
disrupts the activity of GSK-3ß, and the transport of cargo
along neurons becomes uncoordinated,” says lead researcher
Shermali Gunawardena, PhD, an assistant professor of biological
sciences at UB. “This can lead to dangerous
More than 150 mutations of presenilin have been found in
Alzheimer’s patients, and scientists have previously shown
that the protein, when defective, can cause neuronal blockages by
snipping another protein into pieces that accumulate in brain
But this well-known mechanism isn’t the only way
presenilin fuels disease, as Gunawardena’s new study
“Our work elucidates how problems with presenilin could
contribute to early problems observed in Alzheimer’s
disease,” she says. “It highlights a potential pathway
for early intervention through drugs — prior to neuronal loss
and clinical manifestations of disease.”
The study suggests that presenilin activates GSK-3ß. This
is an important finding because the enzyme helps control the speed
at which tiny, organic bubbles called vesicles ferry cargo along
neuronal highways. (You can think of vesicles as trucks, each
powered by little molecular motors called dyneins and
When researchers lowered the amount of presenilin in the neurons
of fruit fly larvae, less GSK-3ß became activated and
vesicles began speeding along cells in an uncontrolled manner.
Decreasing levels of both presenilin and GSK-3ß at once
made things worse, resulting in “traffic jams” as the
bubbles got stuck in neurons.
“Both GSK-3ß and presenilin have been shown to be
involved in Alzheimer’s disease, but how they are involved
has not always been clear,” Gunawardena says. “Our
research provides new insight into this question.”
Gunawardena proposes that GSK-3ß — short for
glycogen synthase kinase-3beta — acts as an “on
switch” for dynein and kynesin motors, telling them when to
latch onto vesicles.
Dyneins carry vesicles toward the cell nucleus, while kinesins
move in the other direction, toward the periphery of the cell. When
all is well and GSK-3ß levels are normal, both types of
motors bind to vesicles in carefully calibrated numbers, resulting
in smooth traffic flow along neurons.
That’s why it’s so dangerous when GSK-3ß
levels are off-kilter, she says.
When GSK-3ß levels are high, too many motors attach to the
vesicles, leading to slow movement as motor activity loses
coordination. Low GSK-3ß levels appear to have the opposite
effect, causing fast, uncontrolled movement as too few motors latch
Both scenarios — too much GSK-3ß or too little
— can result in neuronal blockages.
The study appeared online in Human Molecular Genetics on Oct. 8
and will be published in a forthcoming print edition of the
journal. Funding for the research came from the John R. Oishei
Foundation, a Fulbright Scholarship and fellowships from the
University at Buffalo Center for Undergraduate Research and