Sự ức chế CSF1R cứu vãn bệnh lý tau và sự thoái hóa thần kinh trong mô hình A/T/N với các bệnh lý AD kết hợp, trong khi vẫn bảo tồn tế bào vi mô gắn với mảng bám

Chritica Lodder1, Isabelle Scheyltjens2, Ilie-Cosmin Stancu1, Pablo Botella Lucena1, Manuel Gutiérrez de Ravé1, Sarah Vanherle1, Tim Vanmierlo1, Niels Cremers1, Hannah Vanrusselt1, Bert Brône1, Bernard Hanseeuw3, Jean‐Noël Octave3, Astrid Bottelbergs4, Kiavash Movahedi5, Ilse Dewachter1
1Department of Neurosciences, Biomedical Research Institute, Hasselt University, Hasselt, Belgium
2Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium
3Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium
4Neuroscience Department, Janssen Research and Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium
5Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium

Tóm tắt

Tóm tắtBệnh Alzheimer (AD) được đặc trưng bởi sự tiến triển tuần tự của các mảng bám amyloid (A), các đám rối sợi thần kinh (T) và sự thoái hóa thần kinh (N), cấu thành bệnh lý ATN. Trong khi tế bào vi mô được coi là những yếu tố đóng góp chính vào sinh bệnh học của AD, nhưng vai trò của chúng trong sự hiện diện kết hợp của các bệnh lý ATN vẫn chưa được hiểu hoàn toàn. Là những cảm biến của môi trường vi mô trong não, các kiểu hình tế bào vi mô và vai trò của chúng được xác định quan trọng bởi các bệnh lý trong não, cho thấy nhu cầu cần phân tích chúng trong các mô hình tiền lâm sàng tái hiện các bệnh lý ATN kết hợp, bên cạnh vai trò của chúng chỉ trong các mô hình A và T. Ở đây, chúng tôi báo cáo một mô hình hạt giống tau mới, trong đó bệnh lý amyloid tạo điều kiện cho sự lan truyền tau hai bên liên quan đến sự teo não, từ đó tái hiện rõ nét bệnh lý ATN. Giải trình tự RNA đơn bào cho thấy rằng bệnh lý ATN làm trầm trọng thêm sự kích hoạt tế bào vi mô hướng tới trạng thái tế bào vi mô liên quan đến bệnh, với sự gia tăng đáng kể của Apoe so với các mô hình chỉ có amyloid (A). Quan trọng là, sự ức chế Thụ thể Yếu tố Kích thích thuộc địa 1 ưu tiên loại bỏ tế bào vi mô không gắn với mảng bám so với tế bào vi mô gắn với mảng bám. Sự tiêu giảm ưu tiên các tế bào vi mô không gắn với mảng bám đã làm giảm đáng kể bệnh lý tau và teo thần kinh, cho thấy vai trò có hại của chúng trong quá trình tiến triển ATN. Tóm lại, dữ liệu của chúng tôi tiết lộ những phức tạp của sự kích hoạt tế bào vi mô và các đóng góp của chúng cho bệnh lý trong một mô hình tái hiện các bệnh lý ATN kết hợp của AD. Dữ liệu của chúng tôi có thể cung cấp cơ sở cho các liệu pháp nhắm mục tiêu tế bào vi mô tập trung vào các quần thể tế bào vi mô có hại, đồng thời bảo tồn các quần thể tế bào vi mô bảo vệ.

Từ khóa

#Bệnh Alzheimer #tế bào vi mô #bệnh lý ATN #mô hình tau #ức chế thụ thể CSF1R #amyloid #sự thoái hóa thần kinh

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