(From left) Professor Ricky Wong Man-shing and Dr Li Hung-wing


(左起)黃文成教授和李紅榮博士

In vivo fluorescence images show (above) a seven-month-old healthy mouse and (below) age-matched mouse treated with Alzheimer’s disease at different time points


體內螢光成像顯示,(上)七個月大的健康老鼠和(下)帶病老鼠隨著時間增長,腦內的花青素化合物濃度改變

The reddish powder is the cyanine compound


紅色粉末是花青素化合物

The cyanine compounds dissolved in solution with the presence (left) and absence (right) of amyloid peptide, the Alzheimer’s disease related amyloid peptide.


花青素化合物溶解在水溶液中(右)和添加阿茲海默症相關β-澱粉樣蛋白肽後(左)

Date: 04 Jan 2018 (Thursday)

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HKBU scholars develop world-first array of multifunctional compounds for detection, imaging and treatment of Alzheimer’s Disease

浸大學者研發全球首創 認知障礙症檢測、成像和治療化合物系列

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).

香港浸會大學的化學學者就認知障礙症(又稱阿茲海默症)的檢測、成像和治療,研發出一系列全球首創的多功能「花青素化合物」。這項新發明已獲得四項美國專利和一項中國專利,有關論文並在國際著名學術期刊上刊登。

浸大化學系黃文成教授和副教授李紅榮博士率領的研究團隊,證實結合創新的「花青素化合物」於納米檢測平台上,能定量追蹤人類體液(如腦脊液、血清、唾沫、尿液)中所存在的與阿茲海默症相關的蛋白質生物標記物,準確檢測阿茲海默症,而且檢測成本低、速度快、靈敏度高。另一方面,這種化合物可作為顯影劑,追蹤和檢測患者體內的病變過程,有助進一步了解發病的機理,有極大潛力發展成治療該症的藥物。

阿茲海默症是認知障礙症中最常見的類型,是現時沒有方法治癒的腦神經退化疾病,其致病成因未明。患阿茲海默症的特徵是腦內積聚「澱粉樣蛋白」(又稱「老人斑」)。常用的診斷方法包括臨床評估、認知測試和神經影響(監測大腦的結構變化),但需要在症狀出現後才有效。其他方法如磁力共振成像,則需要將造影劑注射入人體,增加風險。

團隊研製的花青素化合物能夠針對檢測人類腦脊液內的「β-澱粉樣肽」、「tau」和「p-tau」這三種與阿茲海默症相關的蛋白質,而且,只需使用微量(一小滴、約0.001毫升)的檢測試劑滴在腦脊液樣品液中,約一小時便能準確地針對目標蛋白進行定量分析,比現時所用的檢測方法更快,靈敏度更高,而成本亦大大低於現有的方法。

檢測原理是以磁納米顆粒表面的抗體來監測阿茲海默症相關的蛋白質,再加上新開發的花青素化合物進行標記,增加螢光信號,達到量化效果。

李紅榮博士說:「這種新開發的檢測工具成本低,而且能夠精確地診斷並預測阿茲海默症的症狀,亦可作為一種新型非侵入性的方法,用於全民疾病篩查工具,可見這種科學的檢測方法具有非常大的潛力。」

李博士表示,這種新的檢測方法可進一步研究應用到其他相關疾病的抗體、核酸檢測,更廣泛用於疾病診斷和生物醫學研究。

該項研究的論文〈Ultra-sensitive detection of protein biomarkers for diagnosis of Alzheimer’s disease〉已刊登於國際著名學術期刊《Chemical Science》(DOI: 10.1039/C6SC05615F)。

另外,由於這種花青素化合物對β-澱粉樣蛋白肽寡聚體具靶向性,與蛋白結合後能呈現螢光,成為顯影劑,可用於監測患者體內阿茲海默症的變化,更深入理解該症的發病機理。

β-澱粉樣蛋白肽寡聚體是由它的單體錯誤折疊和自我聚合所形成,從而產生β-澱粉蛋白纖維,生成「老人斑」——阿茲海默症的病理學標誌之一。研究顯示,寡聚體這種結構形式是β-澱粉樣物質中最具神經毒性的,並且與形成阿茲海默症關係密切。因此,檢測和成像β-澱粉樣蛋白肽寡聚體比其他任何β-澱粉樣物質更加重要。實驗發現花青素類化合物於年輕的阿爾茲海默症轉基因模型小鼠上,成功進行β-澱粉樣蛋白肽寡聚體檢測和成像,研究團隊將進一步研究其病理。

此外,這種嶄新的化合物能有效穿透腦血管屏障(可進入腦組織)、低毒性,並能抑制β-澱粉樣蛋白有毒的寡聚體,因此可以保護神經細胞免被β-澱粉樣蛋白的毒性侵害。由於該化合物能夠抑制引起神經毒性低聚物的產生,又能保護神經細胞免於活性氧的侵害和細胞內鈣離子的升高,具有可觀的治療潛力。

新化合物對於前期阿茲海默症的診斷和治療有巨大的潛力,研究團隊目前正研究這系列的化合物能否提升阿茲海默症小鼠模型的認知能力。

這研究的論文〈Fluoro-Substituted Cyanine for Reliable in vivo Labelling of Amyloid-β Oligomers and Neuroprotection against Amyloid-β Induced Toxicity〉已刊登於《Chemical Science》(DOI: 10.1039/C7SC03974C)。
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