Alzheimer’s disease is the sixth leading cause of death in the
United States, affecting one in 10 people over the age of 65. Scientists
are engineering nanodevices to disrupt processes in the brain that lead
to the disease.
People who are affected by Alzheimer’s disease have a specific type
of plaque, made of self-assembled molecules called β-amyloid (Aβ)
peptides, that build up in the brain over time. This buildup is thought
to contribute to loss of neural connectivity and cell death. Researchers
are studying ways to prevent the peptides from forming these dangerous
plaques in order to halt development of Alzheimer’s disease in the
brain.
In a multidisciplinary study, scientists at the U.S. Department of Energy’s (
DOE) Argonne National Laboratory, along with collaborators from the Korean Institute of Science and Technology (
KIST) and the Korea Advanced Institute of Science and Technology (
KAIST),
have developed an approach to prevent plaque formation by engineering a
nano-sized device that captures the dangerous peptides before they can
self-assemble.
“We’ve taken building blocks from nanotechnology and biology to engineer a high-capacity ‘cage’ that traps the peptides and clears them from the brain.” — Elena Rozhkova, scientist, Center for Nanoscale Materials
The β-amyloid peptides arise from the breakdown of an amyloid
precursor protein, a normal component of brain cells,” said Rosemarie
Wilton, a molecular biologist in Argonne’s Biosciences division.
“In a healthy brain, these discarded peptides are eliminated.”
In brains prone to the development of Alzheimer’s, however, the brain
does not eliminate the peptides, leaving them to conglomerate into the
destructive plaques.
“The idea is that, eventually, a slurry of
our nanodevices could collect the peptides as they fall away from the
cells — before they get a chance to aggregate,” added Elena Rozhkova, a
scientist at Argonne’s Center for Nanoscale Materials (
CNM), a
DOE Office of Science User Facility.
Decorating the surface
The researchers covered the surface of the new nanodevice with
fragments of an antibody — a type of protein — that recognizes and binds
to the Aβ peptides. The surface of the nanodevice is spherical and
porous, and its craters maximize the available surface area for the
antibodies to cover. More surface area means more capacity for capturing
the sticky peptides.
To find the optimal coating, the scientists first searched previous
literature to identify antibodies that have high affinity to Aβ
peptides. It was important to choose an antibody that attracts the
peptides but doesn’t bind to other molecules in the brain. Then the
team, led by Wilton, produced the antibodies in bacteria and tested
their performance.
A full antibody molecule can be up to a few dozen nanometers long,
which is big in the realm of nanotechnology. However, only a fraction of
this antibody is involved in attracting the peptides. To maximize the
effectiveness and capacity of the nanodevices, Wilton’s group produced
tiny fragments of the antibodies to decorate the nanodevice’s surface.
Engineering and testing the nanodevice
The scientists at
CNM constructed the base
of the porous, spherical nanodevices out of silica, a material that has
long been used in biomedical applications due to its flexibility in
synthesis and its nontoxicity in the body. Coated with the antibody
fragments, the nanodevices capture and trap the Aβ peptides with high
selectivity and strength.
“Many attempts to prevent Alzheimer’s have
focused on inhibiting enzymes from cutting β-amyloid peptides off of the
cell’s surface,” said Rozhkova, who led the project at
CNM.
“Our
elimination approach is more direct. We’ve taken building blocks from
nanotechnology and biology to engineer a high-capacity
‘cage’ that traps the peptides and clears them from the brain.”
At
CNM, the scientists tested the
effectiveness of the devices by comparing how the peptides behaved in
the absence and presence of the nanodevices. Using in vitro transmission
electron microscopy (
TEM), they observed a
notable decline in peptide aggregation in the presence of the
nanodevices. They further analyzed the interactions using confocal laser
scanning microscopy and microscale thermophoresis measurement, two
additional techniques for characterizing interactions at the nanoscale.
The scientists also performed small-angle X-ray scattering to study
the processes that make the nanodevices porous during synthesis. The
researchers performed the X-ray characterization, led by Byeongdu Lee, a
group leader in Argonne’s X-ray Science division, at beamline
12-ID-B of the lab’s Advanced Photon Source (
APS), a
DOE Office of Science User Facility.
These studies supported the case that the nanodevices sequester the peptides from the pathway to aggregation by more than
90 percent
compared to the control silica particles without the antibody
fragments. However, the devices still needed to demonstrate their
effectiveness and safety within cells and brains.
Joonseok Lee — who originally proposed this experiment at Argonne as a
Director’s Postdoctoral Appointee and pioneered the design for the
nanodevice — continued the study of the therapeutic potential of this
device at
KIST and
KAIST.
“The Director’s Postdoctoral Position is a
rare opportunity offered at Argonne that allows for unique research
projects and cross-field collaborations that might not otherwise be
possible,” said Rozhkova.
“We have
incredible minds at the lab who want to explore topics that don’t fall
under a predefined area of research, and this program encourages this
creativity and innovation.”
The in viv
o experiments — experiments that took place in
living cells — performed by Lee and his collaborators showed that the
nanodevices are nontoxic to cells. They also tested the effectiveness of
the devices in the brains of mice with Alzheimer’s, demonstrating
around
30 percent suppression of plaque
formation in brains containing the nanodevices compared to control
brains. The research on mice was conducted at
KIST and
KAIST in South Korea with appropriate government approvals.
This study combined the strengths of antibody engineering and nanotechnology, the power of two
DOE User
Facilities at Argonne and innovative collaboration resulting from the
laboratory’s postdoctoral program to explore a technological approach to
preventing Alzheimer’s.
Using a similar approach, scientists may also be able to pair the
silica nanoparticles with different antibodies that target molecules
related to other neurodegenerative diseases, such as Huntington’s
disease and Parkinson’s disease, which also involve abnormal protein
aggregation. The porous nanoparticles may be further upgraded for use in
imaging applications including fluorescent imaging and magnetic
resonance imaging.
###
A paper on the research, titled
“Silica nanodepletors: Targeting and clearing Alzheimer’s β-amyloid plaques“, was published in the April issue of
Advanced Functional Materials and was featured on its cover.
This research was supported by the Korea Institute of Science and
Technology Institutional Program and the National Research Foundation
via the Creative Research Initiative Center and Basic Science Research
Program, Republic of Korea. The researchers also acknowledge the
Director’s Postdoctoral Fellowship from Argonne National Laboratory.
https://www.eurekalert.org/pub_releases/2020-04/dnl-nft043020.php
