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Chuyển hóa amyloid-β trong các mô hình và bệnh nhân mắc bệnh Niemann-Pick C
Tóm tắt
Bệnh Niemann-Pick loại C (NPC) là một bệnh lyso-some thần kinh tiến triển, có sự thay đổi trong quá trình vận chuyển lipid tế bào. Chuyển hóa amyloid-β (Aβ) – trước đây chủ yếu được nghiên cứu trong bệnh Alzheimer – đã được đề xuất là bị thay đổi trong NPC. Chúng tôi đã thực hiện một đặc trưng chi tiết về các sản phẩm chuyển hóa từ protein tiền thân amyloid (APP) trong các mô hình NPC và bệnh nhân. Chúng tôi đã sử dụng nhiều công nghệ phân tích, bao gồm xét nghiệm miễn dịch và kết tủa miễn dịch sau đó là phổ khối (IP-MS) để đặc trưng hóa các peptide Aβ và các mảnh APP hòa tan (sAPP-α/β) trong môi trường tế bào từ các mô hình tế bào NPC được kích thích bằng hóa học (U18666A) và di truyền (NPC1−/−), cũng như dịch não tủy (CSF) từ mèo NPC và bệnh nhân người. Mẫu peptide Aβ và mảnh sAPP-α/β trong môi trường tế bào bị ảnh hưởng khác nhau bởi kiểu hình NPC do điều trị U18666A và kiểu gen NPC1−/−. Điều trị bằng U18666A đã làm tăng mức độ sAPP-α, AβX-40 và AβX-42 trong môi trường tiết ra và làm giảm mức sAPP-β, Aβ1-40 và Aβ1-42, trong khi IP-MS cho thấy mức tương đối của Aβ5-38 và Aβ5-40 gia tăng trong phản ứng với điều trị. Các tế bào NPC1−/− có mức sAPP-α và Aβ1-16 trong môi trường giảm, và mức sAPP-β tăng. Mèo NPC có sự phân phối Aβ peptide trong CSF bị thay đổi so với mèo bình thường. Mèo được điều trị bằng hợp chất có khả năng thay đổi bệnh 2-hydroxypropyl-β-cyclodextrin có mức Aβ peptide ngắn bao gồm Aβ1-16 gia tăng so với mèo không được điều trị. Bệnh nhân NPC nhận β-cyclodextrin có mức Aβ1-42, AβX-38, AβX-40, AβX-42 và sAPP-β trong CSF giảm dần theo thời gian, cũng như giảm các dấu hiệu tổn thương trục thần kinh tau và tau phosphoryl hóa. Chúng tôi kết luận rằng các mô hình NPC có chuyển hóa Aβ bị thay đổi, nhưng có sự khác biệt giữa các hệ thống thí nghiệm, cho thấy rằng sự mất chức năng NPC1, như trong các tế bào NPC1−/−, hoặc sự rối loạn chức năng NPC1, được thấy ở bệnh nhân và mèo NPC cũng như trong các tế bào điều trị bằng U18666A, có thể gây ra những tác động tinh tế nhưng khác biệt trên các con đường phân hủy APP. Những phát hiện ban đầu từ mèo NPC gợi ý rằng điều trị bằng cyclodextrin có thể có tác động đến các con đường xử lý APP. Các dấu hiệu sinh học Aβ trong CSF, sAPP và tau đã thay đổi một cách linh hoạt theo thời gian ở bệnh nhân NPC người.
Từ khóa
#Niemann-Pick type C #Amyloid-β #APP #tế bào #dịch não tủy #peptide #xét nghiệm miễn dịch #phổ khốiTài liệu tham khảo
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