Tác động của những đột biến hiếm ở AKAP9 đến sự phosphoryl hóa Tau liên quan đến bệnh Alzheimer ở người Mỹ gốc Phi

Journal of Neuroimmune Pharmacology - Tập 13 - Trang 254-264 - 2018
Tsuneya Ikezu1, Cidi Chen2, Annina M. DeLeo1, Ella Zeldich2, M. Daniele Fallin3, Nicholas M. Kanaan4, Kathryn L. Lunetta5, Carmela R. Abraham6,2, Mark W. Logue7,8,9, Lindsay A. Farrer6,5,7,10,11
1Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, USA
2Department of Biochemistry, Boston University School of Medicine, Boston, USA
3Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, USA
4Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, USA
5Department of Biostatistics, Boston University School of Public Health, Boston, USA
6Department of Neurology, Boston University School of Medicine, Boston, USA
7Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, USA
8Department of Psychiatry, Boston University School of Medicine, Boston, USA
9The National Center for PTSD, Behavioral Science Division, VA Boston Healthcare System, Boston, USA
10Department of Ophthalmology, Boston University School of Medicine, Boston, USA
11Department of Epidemiology, Boston University School of Public Health, Boston, USA

Tóm tắt

Chúng tôi đã nghiên cứu ảnh hưởng của hai đột biến hiếm (rs144662445 và rs149979685) trong gen A-kinase anchoring protein 9 (AKAP9), trước đây đã được liên kết với bệnh Alzheimer (AD) ở người Mỹ gốc Phi (AA), đối với các biến đổi sau phiên mã của các phân tử gây bệnh liên quan đến AD, bao gồm protein tiền chất amyloid (APP) và protein liên kết vi ống Tau bằng cách sử dụng các dòng tế bào bạch cầu lympho (LCLs) từ 11 cá thể AA có ít nhất một đột biến AKAP9 và 17 cá thể AA không có những đột biến này. Các LCL đã được chuyển gen bằng các vector virus biểu hiện các đột biến gây bệnh trong APP hoặc Tau dạng hoang dã hoàn chỉnh của con người. Dung dịch tế bào đã được phân tích để xác định tổng APP, Aβ40, và tổng và T181 phosphoryl hóa-Tau (pTau). Các đột biến AKAP9 không có tác động đến tỉ lệ Aβ40/APP, nhưng gây ra sự gia tăng đáng kể tỉ lệ pTau/Tau trong các LCL được điều trị bằng chất ức chế phosphodiesterase-4 rolipram, chất này kích hoạt protein kinase A. Phân tích proteome của tương tác Tau đã cho thấy sự giàu có của các protein liên kết RNA và giảm thiểu các phân tử proteasome trong các tế bào chịu tác động của rolipram với các đột biến AKAP9. Nghiên cứu này cho thấy tác động của các đột biến AKAP9 hiếm gặp đến Tau, một cơ chế trung tâm trong bệnh sinh của AD, trong các LCL lấy từ các cá thể AD và đối chứng.

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