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Khám Phá Các Cơ Chế Thần Kinh Độc Tiềm Năng: Kích Hoạt Tín Hiệu CDK5-p25 Do Pb Gây Ra Trong Sự Phát Triển Của Bệnh Alzheimer, Nhấn Mạnh Việc Ức Chế CDK5 Và Sự Hình Thành Các Chất T毒性 p25
Molecular Neurobiology - Trang 1-14 - 2023
Tóm tắt
Bệnh Alzheimer (AD) là một rối loạn thoái hóa thần kinh phức tạp với nguyên nhân chịu ảnh hưởng bởi nhiều yếu tố di truyền và môi trường. Các kim loại nặng, chẳng hạn như chì (Pb), đã được chỉ ra là có liên quan đến quá trình bệnh lý của AD, nhưng các cơ chế tiềm ẩn vẫn chưa được hiểu rõ. Nghiên cứu này điều tra vai trò tiềm tàng gây thoái hóa thần kinh của Pb và các peptide amyloid β (1–40 và 25–35) thông qua sự tương tác của chúng với kinase phụ thuộc cyclin 5 (CDK5) và chất kích hoạt của nó, p25, nhằm làm sáng tỏ cơ sở phân tử của độc tố thần kinh do Pb gây ra trong các tế bào thần kinh. Để đạt được điều này, một chất ức chế CDK5 đã được sử dụng để ức chế chọn lọc hoạt động của CDK5 và nghiên cứu tác động của nó đối với sự thoái hóa thần kinh. Kết quả cho thấy tiếp xúc với Pb dẫn đến sự gia tăng hấp thụ Pb (56,7% tại 15 μM Pb) và sự rối loạn trong nồng độ canxi nội bào (tăng 19,6% sau điều trị Pb). Các kết quả cũng chỉ ra sự giảm đáng kể trong khả năng chống oxy hóa tổng thể (giảm 88,6% sau điều trị Pb) và cũng có sự gia tăng trong sự cacbon hóa protein (tăng 26,2% sau sự kết hợp điều trị Pb và Aβp), cho thấy thiệt hại oxy hóa, gợi ý về việc phòng vệ tế bào bị suy giảm trước căng thẳng oxy hóa và tăng thiệt hại DNA do oxy hóa (178 pg/ml và 182 pg/ml của 8-OH-dG sau điều trị Pb và All). Thêm vào đó, những rối loạn trong nồng độ calpain, p25-35 và CDK5 đã được quan sát và các dấu hiệu liên quan đến chuyển hóa chất chống oxy hóa (phospho-Peroxiredoxin 1), phản ứng với tổn thương DNA (phospho-ATM và phospho-p53), và sự phá hủy màng nhân (phospho-lamin A/C) cũng được ghi nhận, hỗ trợ vai trò của tín hiệu CDK5-p25 do Pb gây ra trong sự phát triển của AD. Những phát hiện này làm sáng tỏ các sự kiện phân tử phức tạp đứng sau độc tính thần kinh gây ra bởi Pb và cung cấp cái nhìn quý giá vào các cơ chế góp phần vào sự phát triển của AD.
Từ khóa
#Bệnh Alzheimer #độc tính thần kinh #chì #kinase phụ thuộc cyclin #CDK5 #p25 #thiệt hại oxy hóaTài liệu tham khảo
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