(EMBO Mol Med) 中研院(陳佩燁) 鼻噴R8-Aβ(25-35) 降低老鼠阿茲海默症(APP/PS1 double transgenic mice)

新突破﹗胜肽鼻噴劑 可望延緩阿茲海默症 2017-05-05 記者吳柏緯／台北報導 中研院研究團隊近日發表新設計出的胜肽R8-Aβ（25-35）-PEI，可透過鼻腔噴劑投藥，預防或減緩阿茲海默症的病況。此研究成果已刊登在今年3月的國際專業期刊《歐洲分子生物組織之醫學生物》。中研院表示，阿茲海默症的病理特徵是「澱粉樣老年斑塊及神經纖維糾結」，澱粉樣老年斑塊可能在患者發病前20年就開始形成，因此觀察斑塊形成情況是預防阿茲海默症的重要指標。目前國外臨床研究發現，以靜脈注射大量抗體對抗Aβ胜肽（胜肽是蛋白質片段），可有效減少阿茲海默症初期病患腦中老年斑塊的形成，並且減緩智能退化的程度。不過，抗體療法會引發許多副作用，不少病患中途就放棄治療。中研院生化所陳佩燁副研究員帶領的研究團隊，設計出可以抑制Aβ胜肽聚集的另一種胜肽（R8-Aβ（25-35）-PEI）。陳佩燁指出，胜肽在血中穩定性不好，非常容易被血中酵素分解，過去一直是胜肽治療的難題。新設計的胜肽可以穿透細胞膜，不經過循環系統，直接經由鼻嗅覺神經到腦部，以達老年斑塊形成的效果。研究團隊在4個月大，有阿茲海默症的基因轉殖鼠身上進行實用，透過每週鼻腔投藥6次，13個月後發現實驗鼠腦中累積的斑塊量減少，老鼠的記憶能力也比沒有給藥的對照組來得好，顯示此方式可望應用於阿茲海默症的預防或減緩發病。陳佩燁表示，隨著人口老化，阿茲海默症病患人數急遽增加，且確診後仍有4至20年的壽命，對病患家屬及社會造成很大的經濟負擔；如果能延緩發病，將可大幅度地減少家庭及社會的財政支出。

An intranasally delivered peptide drug ameliorates cognitive decline in Alzheimer transgenic mice. EMBO Mol Med. 2017 May;9(5):703-715. Alzheimer's disease (AD) is the most common neurodegenerative disease. Imbalance between the production and clearance of amyloid β (Aβ) peptides is considered to be the primary mechanism of AD pathogenesis. This amyloid hypothesis is supported by the recent success of the human anti-amyloid antibody aducanumab, in clearing plaque and slowing clinical impairment in prodromal or mild patients in a phase Ib trial. Here, a peptide combining polyarginines (polyR) (for charge repulsion) and a segment derived from the core region of Aβ amyloid (for sequence recognition) was designed. The efficacy of the designed peptide, R8-Aβ(25-35), on amyloid reduction and the improvement of cognitive functions were evaluated using APP/PS1 double transgenic mice. Daily intranasal administration of PEI-conjugated R8-Aβ(25-35) peptide significantly reduced Aβ amyloid accumulation and ameliorated the memory deficits of the transgenic mice. Intranasal administration is a feasible route for peptide delivery. The modular design combining polyR and aggregate-forming segments produced a desirable therapeutic effect and could be easily adopted to design therapeutic peptides for other proteinaceous aggregate-associated diseases.