SIRT1 Regulates Tau Expression and Tau Synaptic Pathology

Article type: Research Article

Authors: Yin, Xiaomin^{a; b; 1} | Zhou, Zheng^{a; 1} | Qiu, Yanyan^{a; 1} | Fan, Xing^a | Zhao, Chenhao^a | Bao, Junze^a | Liu, Chenxu^a | Liu, Fei^c | Qian, Wei^{a; b; *}

Affiliations: [a] Department of Biochemistry and Molecular Biology, Medical School, Nantong University, Nantong, Jiangsu, P.R. China | [b] NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, P.R. China | [c] Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA

Correspondence: [*] Correspondence to: Wei Qian, Department of Biochemistry and Molecular Biology, Medical School, Nantong University, Nantong, Jiangsu, P.R. China. E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Background:Amyloid plaques and neurofibrillary tangles are two pathological hallmarks of Alzheimer’s disease (AD). However, synaptic deficits occur much earlier and correlate stronger with cognitive decline than amyloid plaques and neurofibrillary tangles. Mislocalization of tau is an early hallmark of neurodegeneration and precedes aggregations. Sirtuin type 1 (SIRT1) is a deacetylase which acts on proteins including transcriptional factors and associates closely with AD. Objective:The present study investigated the association between SIRT1 and tau expression/tau localization in cells and in mice brains. Methods:Western blot was performed to detected tau, SIRT1, C/EBPα, and GAPDH protein levels. Immunological fluorescence assay was used to assess tau localization in primary cortical neuronal cells. Golgi staining was performed to evaluated dendritic spine morphology in mice brains. Results:In the present study, we found that SIRT1 negatively regulates expression of tau at the transcriptional level through transcriptional factor C/EBPα. Inhibition of the activity of SIRT1 limits the distribution of tau to the neurites. In the meantime, the alteration of dendritic spine morphology is also observed in the brains of SIRT1+/– mice. Conclusion:SIRT1 may be a potential drug target for early intervention in AD.

Keywords: Alzheimer’s disease, post-synapse, SIRT1, tau

DOI: 10.3233/JAD-215118

Journal: Journal of Alzheimer's Disease, vol. 84, no. 2, pp. 895-904, 2021