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Proper brain functions depend on the
intricate interplay of well-coordinated
signaling pathways in brain cells that
are induced by extracellular stimuli. Cell
surface receptors serve as links to trans-
duce signals to the intracellular targets,
and dysregulation of these signaling
events can result in neurodegenerative
diseases. The research undertaken by
Prof Ip, is focused on unraveling molecu-
lar mechanisms essential for modulation
of different brain functions, in particular
neuronal communication as well as
wiring of neural circuit, both critical for
learning and memory. Through research,
Prof Ip and her team are opening doors
to new understanding of the brain struc-
ture and its function to help combat brain
diseases and disorders, many of which are
currently incurable.
EphA4 Breakthrough
Prof Ip and her team had an exciting
breakthrough with their discovery that
cell surface receptor protein EphA4
is a key player in Alzheimer’s disease
pathology. EphA4 regulates the signal-
ing between neurons, and hence brain
plasticity that is vital for normal cognitive
functions including memory. It dampens
neuronal communication through two
mechanisms. The first is morphological,
in reducing the number of communica-
tion points, known as synapses, between
brain cells. The second is biochemical,
by degrading or reducing the number
of neurotransmitter receptors that are
responsible for communication between
excitatory neurons.
Once these mechanisms were
understood, mouse models were used to
confirm the link with Alzheimer’s disease.
The groundbreaking findings were pub-
lished in 2007 and 2011 in
Nature Neuro-
science
, a leading journal in the field.
Chinese Medicine ‘Blockade’
This discovery, the culmination of more
than a decade of research, was closely
followed by a second major breakthrough
– identification of a small molecule de-
rived from a traditional Chinese medicine
herb to block EphA4 activity and rescue
neuronal communication impairment
observed in Alzheimer’s disease. The
team explored ways to block the negative
EphA4 regulatory pathway, turning to a
traditional Chinese medicine library for
potential “blockades”. This translational
stage of the research was funded by the
Hong Kong government’s Innovation and
Technology Commission and the S. H. Ho
Pathological condition
Normal
Foundation. After testing dozens of po-
tential compounds, a hit was identified
from the herb
gou teng
(
Uncaria rhyncho-
phylla)
in collaboration with computer
scientists.
The team prepared the active
molecule and orally administered it
to transgenic model mice exhibiting
Alzheimer’s disease-like pathologies (AD
model mice). The resulting effect was that
neuronal communication was restored
to normal and synaptic impairment was
rescued. The findings were published
in 2014 in
Proceedings of the National
Academy of Sciences
(
PNAS
), and received
worldwide attention and strong media
interest since they represented a potential
new strategy for developing treatments
for Alzheimer’s disease.
Fresh Light on IL-33
Another recent significant discovery by
Prof Ip and her team may be a potential
game-changer in the approach to devel-
oping therapies for Alzheimer’s disease.
The team demonstrated the importance
of the immune function in the disease
Prof Nancy Ip reviewing
experimental data with
her students.
Proper neuronal architecture and communication is integral for normal circuit activity and brain function.
Synapse
Neuron
Circuit
Network
The left two panels illustrate hippocampal neurons and the
large number of synapses at one hippocampal neuron. Prof Ip
demonstrated that aberrant activity of the cell surface receptor
EphA4 at the synapses on the hippocampal neurons results in
synaptic dysfunctions in mouse models of Alzheimer’s disease
(above two panels). Thus, EphA4 inhibitors to block EphA4 activity
can be developed as a therapeutic approach for Alzheimer’s disease.
