Researchers at the Hong Kong University of Science and Technology (HKUST) have identified new therapeutic targets for Alzheimer'’'s disease (AD) by studying the patients’ brain with a newly-developed methodology. This novel approach also enables researchers to measure the effects of potential drugs on AD patients, opening new directions for AD research and drug development.
Although the pathological mechanisms of AD have been studied for decades, the disease remains incurable. One reason is that conventional research approaches have limited capability to identify molecular targets for drug development. Molecular and pathological pathway analysis generally examines AD patients’ brain as a single unit, which usually underestimates the contributions of different brain cell types to AD and any abnormalities in them. This is especially the case with less-common cell types such as microglia (the brain’s resident immune cells) and neurovascular cells (specifically endothelial cells), which only account for less than 5% and 1% of the total brain cell population, respectively.
However, a team led by Prof. Nancy Ip, Vice-President for Research and Development, Director of the State Key Laboratory of Molecular Neuroscience, and Morningside Professor of Life Science at HKUST, has more than circumvented this problem––they have also identified several new potential molecular targets in endothelial cells and microglia for AD drug development.
The team examined the functions of specific cell types in the postmortem brains of AD patients, which is typically impossible with conventional approaches, by using cutting-edge, single-cell transcriptome analysis, which can be used to characterize of the molecular changes in single cells. This yielded a comprehensive profile of the cell-type-specific changes in the transcriptome in the brains of AD patients. Subsequent analysis identified cell subtypes and pathological pathways associated with AD, highlighting a specific subpopulation of endothelial cells found in the brains’ blood vessels. Accordingly, the team discovered that increased angiogenesis (the formation of new blood vessels from current ones) and immune system activation in a subpopulation of endothelial cells are associated with the pathogenesis of AD, suggesting a link between the dysregulation of blood vessels and AD. The researchers also identified novel targets for restoring neural homeostasis (the ability to maintain a relatively stable internal state despite external changes) in AD patients.
The team also leveraged their single-cell transcriptome analysis to study the mechanism by which the cytokine interleukin-33 (IL-33), an important protein for immune signaling, exerts beneficial actions, making it a possible AD therapeutic intervention. The researchers found that IL-33 reduces AD-like pathology by stimulating the development of a specific subtype of microglia that helps clear amyloid-beta, a neurotoxic protein found in AD brains. The team is also the first to capture data on the mechanisms by which microglia transform into an amyloid-beta–consuming phagocytic state, which is a major cellular mechanism for the removal of pathogens.
“The complex and heterogeneous cell composition within the brain makes it difficult to study disease mechanisms,” Prof. Ip explained. “The advancement of single-cell technology has enabled us to identify specific cell subtypes and molecular targets, which is critical for developing new interventions for Alzheimer’s disease.”
AD, the predominant form of dementia, currently affects over 50 million individuals worldwide and is projected to afflict 150 million people by 2050. Its pathological hallmarks include the accumulation of extracellular amyloid-beta depositions and neurofibrillary tangles. Over time, ineffective clearance of these pathological hallmarks leads to cellular dysfunction in AD, resulting in memory loss, communication problems, reduced physical abilities, and eventually death.
HKUST
HKUST Scientists Make Breakthrough Discovery of New Therapeutic Targets for Alzheimer's Disease
科大發現阿爾茲海默症治療新靶標
Researchers at the Hong Kong University of Science and Technology (HKUST) have identified new therapeutic targets for Alzheimer'’'s disease (AD) by studying the patients’ brain with a newly-developed methodology. This novel approach also enables researchers to measure the effects of potential drugs on AD patients, opening new directions for AD research and drug development.
Although the pathological mechanisms of AD have been studied for decades, the disease remains incurable. One reason is that conventional research approaches have limited capability to identify molecular targets for drug development. Molecular and pathological pathway analysis generally examines AD patients’ brain as a single unit, which usually underestimates the contributions of different brain cell types to AD and any abnormalities in them. This is especially the case with less-common cell types such as microglia (the brain’s resident immune cells) and neurovascular cells (specifically endothelial cells), which only account for less than 5% and 1% of the total brain cell population, respectively.
However, a team led by Prof. Nancy Ip, Vice-President for Research and Development, Director of the State Key Laboratory of Molecular Neuroscience, and Morningside Professor of Life Science at HKUST, has more than circumvented this problem––they have also identified several new potential molecular targets in endothelial cells and microglia for AD drug development.
The team examined the functions of specific cell types in the postmortem brains of AD patients, which is typically impossible with conventional approaches, by using cutting-edge, single-cell transcriptome analysis, which can be used to characterize of the molecular changes in single cells. This yielded a comprehensive profile of the cell-type-specific changes in the transcriptome in the brains of AD patients. Subsequent analysis identified cell subtypes and pathological pathways associated with AD, highlighting a specific subpopulation of endothelial cells found in the brains’ blood vessels. Accordingly, the team discovered that increased angiogenesis (the formation of new blood vessels from current ones) and immune system activation in a subpopulation of endothelial cells are associated with the pathogenesis of AD, suggesting a link between the dysregulation of blood vessels and AD. The researchers also identified novel targets for restoring neural homeostasis (the ability to maintain a relatively stable internal state despite external changes) in AD patients.
The team also leveraged their single-cell transcriptome analysis to study the mechanism by which the cytokine interleukin-33 (IL-33), an important protein for immune signaling, exerts beneficial actions, making it a possible AD therapeutic intervention. The researchers found that IL-33 reduces AD-like pathology by stimulating the development of a specific subtype of microglia that helps clear amyloid-beta, a neurotoxic protein found in AD brains. The team is also the first to capture data on the mechanisms by which microglia transform into an amyloid-beta–consuming phagocytic state, which is a major cellular mechanism for the removal of pathogens.
“The complex and heterogeneous cell composition within the brain makes it difficult to study disease mechanisms,” Prof. Ip explained. “The advancement of single-cell technology has enabled us to identify specific cell subtypes and molecular targets, which is critical for developing new interventions for Alzheimer’s disease.”
AD, the predominant form of dementia, currently affects over 50 million individuals worldwide and is projected to afflict 150 million people by 2050. Its pathological hallmarks include the accumulation of extracellular amyloid-beta depositions and neurofibrillary tangles. Over time, ineffective clearance of these pathological hallmarks leads to cellular dysfunction in AD, resulting in memory loss, communication problems, reduced physical abilities, and eventually death.
EurekAlert! BrightSurf Science News News-Medical.Net MiragePNAS
Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer's disease (Reference Reading)
Cell Reports
IL-33-PU.1 Transcriptome Reprogramming Drives Functional State Transition and Clearance Activity of Microglia in Alzheimer's Disease (Reference Reading)
香港傳媒報導
科大利用新研究方法 發現治療阿茲海默症新靶標
阿茲海默症是一種常見的腦部退化性疾病，目前全球患者人數已超過5000萬，預計到2050年將會增加至1.5億。香港科技大學研究團隊利用一個研究大腦的嶄新方法，不但有助評估潛在藥物對阿茲海默症(AD)患者的作用，更因而發現治療AD的新靶標，為阿茲海默症的研究及藥物開發開闢新路徑。研究成果已在國際權威科學期刊《美國國家科學院院刊》和《細胞報告》發表。
傳統的研究方法在判斷分子靶標是否可應用於藥物開發方面存有一定的局限性。在分子和病理研究中，AD患者腦部會被當作一個整體進行分析，但不同類型的腦細胞以及其異變對AD的作用，卻往往因此而被忽視，尤其是一些數量較少、例如僅佔腦細胞總數5％的小膠質細胞及1％的內皮細胞等。
由科大研究與發展副校長、分子神經科學國家重點實驗室主任及生命科學部晨興教授葉玉如領導的研究團隊，利用先進的單細胞轉錄組分析技術，分析AD患者遺體大腦中特定細胞的功能。這項技術讓研究人員在單細胞水平上追蹤傳統工具無法觀測到的大腦分子變化。研究團隊對AD患者大腦中特定細胞的轉錄組變化作了全面分析，找到與AD相關的細胞亞型和病理途徑，並發現在大腦血管中內皮細胞亞群的作用。研究首次發現血管自然的增新程序和內皮細胞亞群中的免疫激活與AD的發病機理有關連，顯示血管失調與阿茲海默症之間存在聯繫。研究還發現新型分子靶標，有助恢復AD患者的神經動態平衡。
此外，團隊亦利用相關技術分析細胞因子白介素33（IL-33）的作用機制。IL-33是重要的免疫訊號蛋白，有機會發展成為有效治療AD的新藥物。研究人員發現，IL-33可以通過刺激小膠質細胞特定亞型的生長，促進對澱粉樣蛋白的清除，從而改善阿茲海默症的病理特徵。團隊更在小膠質細胞轉化為一個負責去除病原體的吞噬狀態機制方面，取得了突破性成果。
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中国新闻网
香港科技大学发现阿尔茨海默病治疗新靶标
中新社香港11月5日电 香港科技大学(科大)5日表示，该校研究团队设计了一个研究大脑的崭新方法，不但有助评估潜在药物对阿尔茨海默病(AD)患者的作用，更因而发现了治疗AD的新靶标，为阿尔茨海默病的研究及药物开发开辟新路径。
据科大当日发布的新闻稿指出，关于阿尔茨海默病的病理机制研究已开展了数十年，但至今仍未有有效治疗方法。传统的研究方法在判断分子靶标是否可应用于药物开发方面存有一定的局限性。例如在分子和病理研究中，AD患者脑部会被当作一个整体进行分析，但不同类型的脑细胞以及其异变对AD的作用，却往往因此而被忽视，尤其是一些数量较少、如仅占脑细胞总数5%的小胶质细胞及1%的内皮细胞等。
科大表示，由科大研究与发展副校长、分子神经科学国家重点实验室主任及生命科学部晨兴教授叶玉如领导的研究团队，近日不仅解决了这个问题，更同时在内皮细胞和小胶质细胞发现了多个潜在的新分子靶标，可用于开发治疗AD的药物。
叶玉如的团队利用先进的单细胞转录组分析技术，分析AD患者遗体大脑中特定细胞的功能。这项技术让研究人员在单细胞水平上追踪传统工具无法观测到的大脑分子变化。研究团队对AD患者大脑中特定细胞的转录组变化作了全面分析，找到与AD相关的细胞亚型和病理途径，并发现在大脑血管中内皮细胞亚群的作用。
科大表示，研究首次发现血管自然的增新程序和内皮细胞亚群中的免疫启动与AD的发病机理有关联，显示血管失调与阿尔茨海默病之间存在联系。研究还发现了新型分子靶标，有助恢复AD患者的神经动态平衡。(完)
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