2018-01-05
HKBU scholars develop world-first array of multifunctional compounds for detection, imaging and treatment of Alzheimer’s Disease
HKBU Chemistry scholars have invented a new class of
multifunctional cyanine compounds that can be used for detection,
imaging and thus treatment of Alzheimer’s disease. The discovery has
been granted four US patents and a patent by the Chinese government.
Research papers relating to the study were published in a renowned
international academic journal.
The research team was jointly led by Professor Ricky Wong Man-shing and
Associate Professor Dr Li Hung-wing with members from the Department of
Chemistry of HKBU. By making use of the proprietary compounds, the HKBU
team, on one hand, has proved that the cyanine compounds applied onto a
“nano”-detection platform can quantify trace amounts of Alzheimer’s
disease related protein biomarkers present in human fluids such as
cerebrospinal fluid, serum, saliva, and urine. It is a rapid, low-cost
and ultrasensitive detection assay. On the other hand, the compounds
also serve as an imaging agent for in vivo detection and monitoring of
disease progression and understanding the disease pathogenesis as well
as a drug candidate for treatment of the disease.
Alzheimer’s disease is the most common neurodegenerative disorder, it is
incurable and the underlying cause is still not well understood.
Alzheimer’s disease is characterized by the formation of amyloid plaque
in human brains. Clinical evaluation, cognitive tests and neuroimaging
(monitoring the brain’s structural changes) are commonly used to
diagnose Alzheimer’s disease, but are only effective after symptoms
appear. Moreover, neuroimaging, such as magnetic resonance imaging
(MRI), requires injecting contrast agents into a person that may bring
health risks.
The proteins of interest, namely beta amyloid peptide, tau, and p-tau,
in human’s cerebrospinal fluid are linked to Alzheimer’s disease. The
versatile detection assay using the compounds developed by the team
requires only a minute amount of the sample fluids (a few microliters)
to reliably quantify the target proteins. The detection assay developed
by the team is fast, cheaper and more sensitive than traditional
commercially available biological methods.
Detection is based on the specific immuno-interactions between the
target antigen and detection antibody that is immobilised on the surface
of magnetic nanoparticles. The sandwiched immuno-assembly is then
labeled with a newly developed turn-on cyanine compound that enhances
the fluorescence signal, which is quantified by an imaging system.
Dr Li said, “This newly developed assay will be particularly useful as a
low-cost yet accurate diagnostic and prognostic tool for Alzheimer’s
disease. It can also serve as a novel alternative non-invasive tool for
population-wide screening for the disease. This scientific detection
assay has a high potential to serve as a practical diagnosis tool.”
Dr Li said that the new approach is universal and general enough to be
readily modified and elaborated further, such as replacing the
antibodies with other disease-associated antibodies, nucleic acids, for a
broad range of biomedical research and disease diagnostics.
The study entitled “Ultra-sensitive detection of protein biomarkers for
diagnosis of Alzheimer’s disease” was published in internationally
renowned academic journal Chemical Science (DOI: 10.1039/C6SC05615F).
In another related study, the research team discovered the cyanine
compound that exhibits unique targeting on oligomers of beta-amyloid
peptides and the strong fluorescence enhancement upon binding can serve
as an imaging agent for in vivo detection and monitoring of disease progression and understanding the disease pathogenesis.
The beta-amyloid oligomers are formed from misfolding and
self-aggregation of beta-amyloid peptide monomers, which grow further in
size, giving rise to beta-amyloid fibrils and then senile plaques — one
of the pathological hallmarks of Alzheimer’s disease. Studies have
shown that oligomeric form are the most neuro-toxic beta-amyloid species
and closely associated with the disease. Therefore, it is important to
detect and image oligomers of beta-amyloid peptides more than any other
kind of beta-amyloid. This compound has been successfully applied to
detect and image beta-amyloid oligomers in young Alzheimer’s disease
transgenic mice models where the disease-like pathology has just
developed.
Furthermore, this newly developed compound displays excellent
blood-brain barrier permeability, low bio-toxicity, good inhibitory
effect on preventing beta-amyloid monomers from self-aggregation and
forming toxic oligomers as well as excellent neuroprotection effect
against beta-amyloid-induced toxicities. Since this compound can
suppress the neuro-toxic oligomer formation and exert protection against
the reactive oxygen species generation and calcium elevations of
intracellular calcium ion, it shows great therapeutic potential.
This probe offers promising potential as a useful theranostic agent in
early-stage diagnostics and therapeutics for Alzheimer’s disease. The
research team is currently studying in vivo efficacy on cognitive
improvement in Alzheimer’s disease mouse model.
The study entitled “Fluoro-Substituted Cyanine for Reliable in vivo
Labelling of Amyloid-β Oligomers and Neuroprotection against Amyloid-β
Induced Toxicity” was published in Chemical Science (DOI: 10.1039/C7SC03974C).