Tau Acetylation in Entorhinal Cortex Induces its Chronic Hippocampal Propagation and Cognitive Deficits in Mice

Article type: Research Article

Authors: Wang, Xin^a | Liu, En-Jie^a | Liu, Qian^a | Li, Shi-Hong^a | Li, Ting^a | Zhou, Qiu-Zhi^a | Liu, Yan-Chao^a | Zhang, Huaqiu^{b; *} | Wang, Jian-Zhi^{a; c; *}

Affiliations: [a] Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China | [b] Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China | [c] Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China

Correspondence: [*] Correspondence to: Huaqiu Zhang, Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. E-mail: [email protected] and Jian-Zhi Wang, Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Tel./Fax: +86 27 83693883; E-mail: [email protected].

Abstract: Background:Increased tau acetylation at K174, K274, K280, and K281 has been observed in the brains of Alzheimer’s disease (AD) patients or in transgenic mice, but the role of acetylation in tau propagation is elusive. Objective:To study the effect of tau acetylation in entorhinal cortex on tau transmission and learning and memory. Methods:Stereotactic brain injection, behavioral test, electrophysiological recording, immunohistochemistry, and immunofluorescence were used. Results:We constructed the hyperacetylation mimics of tau (AAV-Tau-4Q), the non-acetylation tau mutant (AAV-Tau-4R), and the wild-type tau (AAV-Tau-WT). By overexpressing these different tau proteins in the entorhinal cortex (EC) of 2-month-old mice, we found that overexpressing Tau-4Q in EC for 3 or 6 months (to 5 or 8 months of age) neither induces tau propagation to dentate gyrus (DG) nor glial activation in DG, nor spatial memory deficit. However, overexpressing Tau-WT and Tau-4Q in EC for 13.5 months (15.5 months of age) at 2 months promoted tau propagation respectively to granulosa and hilus of DG with glial activation, synaptic dysfunction, and memory deficit, while overexpressing Tau-4R abolished tau propagation with improved cellular pathologies and cognitive functions. Furthermore, overexpressing Tau-4Q in unilateral DG of 2-month-old mice for 8 weeks also promoted its contralateral transmission with glial activation, and mice with tau (Tau-WT, Tau-4Q, and Tau-4R) overexpression in DG showed cognitive deficits compared with the empty vector controls. Conclusion:Tau acetylation induces a time-dependent propagation from EC to DG, and only hippocampus but not EC tau accumulation induces cognitive deficits.

Keywords: Acetylation, Alzheimer’s disease, neuroglia, propagation, tau

DOI: 10.3233/JAD-200529

Journal: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 241-255, 2020