News Express: UM join forces to develop new treatment for Alzheimer’s disease
cravinachong2024-05-14T18:32:18+08:00
mAb2A7有效減少了PS19小鼠病理性tau聚集、不可溶tau蛋白量、減輕了腦萎縮、小膠質細胞增生、並且有效恢復了PS19小鼠大腦中的蛋白穩態。
mAb2A7 effectively reduces pathological tau aggregation, insoluble tau protein levels, and alleviates brain atrophy and microglia proliferation in PS19 mice, while effectively restoring proteostasis in the brains of PS19 mice
澳大聯合開發阿爾茲海默病新療法
澳門大學健康科學學院助理教授明晨、廈門大學教授趙穎俊及空軍軍醫大學唐都醫院神經內科副教授張巍的研究團隊在阿爾茲海默病（Alzheimer’s disease，AD）研究取得突破性進展，開發出一種有效且副作用較小的阿爾茲海默病潛在療法。相關研究已在神經科學頂級期刊《神經元》（Neuron）上刊登。
AD是最常見的癡呆形式，約佔癡呆症病例的60-70%，在老年人口中是一個主要的致命疾病。其病理特徵包括澱粉樣斑塊、神經纖維纏結（NFT）、神經元丟失引起的腦萎縮等。目前市面上的AD治療藥物只能適度緩解認知障礙，無法阻止腦萎縮和神經元丟失。近年有研究發現，某些磷酸化tau（p-tau）形式（如p-tau181和p-tau217）在AD早期就明顯增加，並可作為早期診斷的生物標記，但其在AD發展中的具體作用仍不明確。
研究團隊篩選出特異性、高親和力結合p-tau217的抗體mAb2A7，發現該抗體能在AD患者腦組織切片中檢測到神經纖維纏結、神經纖維絲和Aβ斑塊周圍的病理。通過單分子免疫檢測技術（SMID），研究人員發現與非癡呆對照組相比，p-tau217在AD患者的腦脊液和血漿中升高。進一步分析發現，AD患者腦脊液中p-tau217水平與其海馬萎縮及認知損傷正相關，與Aβ42/Aβ40的比值呈明顯負相關。這些結果表明p-tau217與AD的神經退行性病變及澱粉樣變密切相關，提示其可能是干預AD神經退變的靶點。
研究人員對抗體給藥的途徑進行探索，結果發現鼻腔給藥能更高效的將抗體遞送進入小鼠大腦，並使其更有效的與靶蛋白結合。通過一系列的動物實驗和生化實驗驗證明了p-tau217是干預AD神經退行性病變的潛在靶點，靶向p-tau217的被動免疫治療是一種干預AD神經退變的行之有效且副作用較小的潛在治療策略，為AD防治提供了新的思路。定量蛋白質組學分析結果進一步顯示，mAb2A7治療主要通過上調突觸和神經元功能相關通路的蛋白表達，以及下調氧化應激及凋亡相關通路的蛋白表達，恢復了PS19小鼠大腦中的蛋白穩態。這些發現強調了恢復蛋白質穩態在AD治療中的重要性。
研究強調的是靶向磷酸化tau蛋白治療AD的潛力，且相對靶向總tau，靶向p-tau217具有更小的副作用。研究揭示p-tau217在tau病理發生和神經變性中發揮關鍵作用，並開發了一種有效且副作用較低的潛在AD免疫治療策略。研究成果在生物學領域備受矚目，已被《科技日報》、《廈門日報》、《遺傳》等雜誌報刊報導，以及在Alzforum、BioArt、生物探索等眾多知名生物學社交平台上被廣泛討論。
明晨、張巍、廈門大學博士後張登虹和碩士生高旭恒為共同第一作者，趙穎俊為通訊作者。廈門大學教授張雲武和張天英，重慶醫科大學教授王超，廈門大學附屬第一醫院教授王占祥及博士生袁輝龍、毛欣茹、王春萍、邵琳、林志豪等做出了重要貢獻。研究團隊特別感謝廈門大學神經科學研究所創始人許華曦教授在研究初期提供的寶貴建議和悉心指導，以及協和腦庫和浙江大學腦庫為研究提供了重要的患者樣本。該研究由澳門大學（檔案編號：SRG2023-00003-FHS）資助。原文可瀏覽https://www.cell.com/neuron/fulltext/S0896-6273(24)00127-2。
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UM join forces to develop new treatment for Alzheimer’s disease
The research teams led by Ming Chen, assistant professor in the Faculty of Health Sciences (FHS) at the University of Macau (UM), Zhao Yingjun, professor at Xiamen University, and Zhang Wei, associate professor in the Department of Neurology at Tangdu Hospital of Air Force Medical University, have made a breakthrough in Alzheimer’s disease (AD) research. They have developed a potentially effective treatment for AD with fewer side effects. The research findings have been published in the top neuroscience journal Neuron.
AD is the most common form of dementia, accounting for around 60-70% of dementia cases, and is one of the leading causes of death in the elderly population. Its pathological features mainly include plaque accumulation, neurofibrillary tangles (NFTs), and brain atrophy caused by neuronal loss. The drugs currently approved for clinical treatment of AD can only moderately alleviate cognitive impairment in AD patients but cannot prevent brain atrophy and neuronal loss. Previous studies have shown that certain forms of phosphorylated tau (p-tau) (such as p-tau181 and p-tau217) increase significantly in the early stages of AD and can be used as biomarkers for early diagnosis of AD, but their role in the onset and progression of AD is still unclear.
The researchers first screened out the antibody mAb2A7, which specifically targets p-tau217 with high affinity, and found that the antibody could detect neurofibrillary tangles, neuropil threads, and dystrophic neurite-like pathology surrounding Aβ plaques in AD patients’ brain tissue sections. Using single-molecule immunoassay technology (SMID), the researchers found that p-tau217 was elevated in the cerebrospinal fluid and plasma of AD patients compared with non-AD controls. Further analysis revealed that p-tau217 levels in the cerebrospinal fluid of AD patients were positively correlated with their hippocampal atrophy and cognitive impairment, and significantly negatively correlated with the Aβ42/Aβ40 ratio. These results indicate that p-tau217 is closely associated with neurodegenerative changes and amyloid pathology in AD, suggesting that it may be a target for intervention of AD neurodegeneration.
The researchers investigated different methods of antibody administration and found that intranasal administration could deliver the antibodies to the mouse brain and make them bind to the target protein more efficiently. A series of animal experiments and biochemical experiments demonstrated that p-tau217 is a potential target for intervention of AD neurodegenerative changes, and that passive immunotherapy targeting p-tau217 is a potentially effective therapeutic strategy for interfering with AD neurodegeneration with fewer side effects, offering a new approach for the prevention and treatment of AD. Quantitative proteomic analysis further showed that mAb2A7 treatment restored protein homeostasis in the brains of PS19 mice, mainly by upregulating the protein expression of pathways related to synaptic and neuronal function and downregulating the protein expression of oxidative stress and apoptosis-related pathways. These findings underline the importance of restoring protein homeostasis in treating AD.
The study highlights the potential of targeting phosphorylated tau protein for AD treatment, and the fact that targeting p-tau217 has fewer side effects than targeting total tau. The study demonstrates that p-tau217 protein plays a key role in tau pathogenesis and neurodegeneration, and develops a potentially effective immunotherapeutic strategy for AD with fewer side effects. The research findings have attracted much attention in the field of biology. They have been featured in newspapers and journals such as Science and Technology Daily, Xiamen Daily, and Genetics. They have also been widely discussed on many well-known social platforms in the field, such as Alzforum, BioArt, and Biodiscover.
Ming Chen, Zhang Wei, Zhang Denghong, postdoctoral fellow at Xiamen University, and Gao Xuheng, master’s student at Xiamen University, are co-first authors, and Zhao Yingjun is the corresponding author. Zhang Yunwu and Zhang Tianying, professors at Xiamen University; Wang Chao, professor at Chongqing Medical University; Wang Zhanxiang, professor at the First Affiliated Hospital of Xiamen University; and Yuan Huilong, Mao Xinru, Wang Chunping, Shao Lin, Lin Zhihao, doctoral students at the First Affiliated Hospital of Xiamen University, also made important contributions to the research. The research teams would like to thank Xu Huaxi, professor and founder of the Institute of Neuroscience at Xiamen University, for his advice and guidance during the early stages of the research, as well as the Brain Bank of Chinese Academy of Medical Sciences & Peking Union Medical College and the China Brain Bank of Zhejiang University School of Medicine for providing important patient samples for the study. The research project was supported by UM (File no: SRG2023-00003-FHS). The full version of the research article is available at https://www.cell.com/neuron/fulltext/S0896-6273(24)00127-2.
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