Nhắm vào các vi mạch nhạy cảm ở vùng hải mã bụng của chuột biến đổi gen đực để khôi phục trí nhớ xã hội giảm sút do chứng Alzheimer

Huiyang Lei1, Guilin Pi2, Ting He1, Rui Xiong1, Jingru Lv1, Jiale Liu1, Dongqin Wu1, Mengzhu Li1, K. Shi1, Shihong Li1, Ning Yu1, Yang Gao1, Huapeng Yu1, Linyu Wei1, Xin Wang1, Qiuzhi Zhou1, Ping Zou1, Jianfeng Zhou1, Yingzhou Liu1, Na Shen1, Jitao Yang1, Dan Ke1, Qun Wang1, Gong‐Ping Liu1, Xifei Yang3, Jian‐Zhi Wang4, Ying Yang1
1Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
2Department of Traditional Chinese Medicine, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430014, China
3Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, Guangdong, China
4Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, 226000, Jiangsu, China

Tóm tắt

Tóm tắt Đặt vấn đề Mất trí nhớ hồi tưởng là một biểu hiện lâm sàng nổi bật của bệnh Alzheimer (AD), có liên quan chặt chẽ đến bệnh lý tau và sự suy giảm của hải mã. Do sự đa dạng của các tế bào thần kinh não, vai trò cụ thể của các tế bào thần kinh khác nhau về độ nhạy cảm với sự tích tụ tau và sự đóng góp của chúng vào việc giảm trí nhớ xã hội giống như AD vẫn còn chưa rõ ràng. Do đó, cần có thêm các nghiên cứu tiếp theo. Phương pháp Chúng tôi đã nghiên cứu tác động của bệnh lý tau như AD thông qua phân tích proteomic và phosphoproteomic bằng TAg khối lượng, các bài kiểm tra hành vi xã hội, điện sinh lý học hải mã, nhuộm miễn dịch huỳnh quang và ghi nhận quang học trong cơ thể GCaMP6f và iGABASnFR. Ngoài ra, chúng tôi đã sử dụng công nghệ quang gen và cho uống axit ursolic (UA) để kiểm tra tác động của các tác nhân này lên trí nhớ xã hội ở chuột. Kết quả Kết quả phân tích proteomic và phosphoproteomic đã chỉ ra các đặc điểm của CA1 hải mã bụng (vCA1) dưới cả điều kiện sinh lý và bệnh lý tau giống như AD. Khi tau dần dần tích tụ, vCA1, đặc biệt là các tế bào thần kinh kích thích và parvalbumin (PV), đã bị đầy ắp tau sai vị trí và phosphoryl hóa (p-Tau). Phát hiện này không được quan sát thấy ở CA1 hải mã lưng (dCA1). Sự quá biểu hiện của tau người (hTau) trong các tế bào thần kinh kích thích và PV giống như tích tụ tau giống như AD, ức chế đáng kể sự kích thích thần kinh và giảm sự phân biệt liên quan đến sự phát bắn của các tế bào thần kinh này trong vCA1. Kích hoạt ánh sáng các tế bào thần kinh kích thích và PV trong vCA1 ở các nhịp điệu và khoảng thời gian cụ thể một cách hiệu quả đã cải thiện trí nhớ xã hội bị suy giảm do tau. Đáng chú ý, 1 tháng sử dụng UA đã giảm hiệu quả sự tích tụ tau qua quá trình tự thực bào theo cách phụ thuộc vào yếu tố phiên mã EB (TFEB) và khôi phục lại vi mạch vCA1 để cải thiện trí nhớ xã hội bị suy giảm do tau. Kết luận Nghiên cứu này đã làm sáng tỏ mạng lưới protein và phosphoprotein khác nhau giữa dCA1 và vCA1 và nêu bật sự nhạy cảm của vi mạch vCA1 đối với sự tích tụ tau giống như AD. Đáng chú ý, những phát hiện mới của chúng tôi về hiệu quả của UA trong việc giảm tải tau và nhắm vào vi mạch vCA1 có thể cung cấp một chiến lược hứa hẹn để điều trị AD trong tương lai.

Từ khóa


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