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Alix và Syntenin-1 hướng dẫn sự vận chuyển protein tiền chất amyloid vào các vesicle ngoại bào
Tóm tắt
Quá trình vận chuyển nội sinh và cắt đứt amyloid của protein tiền chất amyloid (APP) được cho là đóng vai trò trong sự thoái hóa thần kinh quan sát được ở bệnh Alzheimer (AD). Bằng chứng gần đây đã gợi ý rằng việc đóng gói và tiết APP cũng như các sản phẩm cắt đứt amyloid của nó vào các vesicle ngoại bào nhỏ (EVs) có thể tạo điều kiện cho việc tiếp nhận các yếu tố độc hại này trong quá trình bệnh lý. Tuy nhiên, các cơ chế phân tử liên quan đến quá trình vận chuyển APP vào EVs vẫn chưa được hiểu rõ. Trong nghiên cứu này, cơ chế và tác động của việc vận chuyển APP vào các vesicle ngoại bào (EVs) đã được đánh giá thông qua một loạt các bài knockdown gen có thể kích thích. Chúng tôi chứng minh rằng các protein liên kết với vesicle Alix và Syntenin-1 là thiết yếu cho việc định vị đúng trong tế bào và việc tiết EV hiệu quả của APP thông qua một con đường không cần phức hợp phân loại nội bào thiết yếu cho vận chuyển (ESCRT). Mảnh fragment C-terminal độc hại (CTFβ) của APP cũng được tiết ra liên quan đến các vesicle nhỏ. Những cơ chế này được bảo tồn trong các tế bào giống nơron đã biệt hóa cuối cùng. Hơn nữa, việc knockdown Alix và Syntenin-1 làm thay đổi vị trí tế bào của APP, giữ protein tiền chất trong lưới nội sinh và các khoang nội bào lysosome. Cuối cùng, việc chuyển giao các EV nhỏ chứa APP đột biến gây ra sự tăng sản xuất các loại oxy phản ứng và độc tính thần kinh đối với các tế bào nơron vỏ não được tạo ra từ tế bào gốc đa năng cảm ứng của con người và các nơron nguyên phát chưa được phân hóa, hiệu ứng này được cải thiện khi giảm Alix và Syntenin-1. Tóm lại, những phát hiện này làm sáng tỏ một cơ chế mới để hiểu rõ hơn về việc vận chuyển nội bào của APP và CTFβ vào các vesicle ngoại bào được tiết ra, cũng như tác động tiềm tàng của nó đối với độc tính thần kinh trong bối cảnh bệnh amyloidopathy Alzheimer.
Từ khóa
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