Hong Kong Baptist University (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).