PKA-CREB Signaling Suppresses Tau Transcription

Article type: Research Article

Authors: Liu, Huanliang^{a; b; 1} | Jin, Xiaoxia^{b; 1} | Yin, Xiaomin^{a; b} | Jin, Nana^{b; c} | Liu, Fei^{b; c; *} | Qian, Wei^{a; b; *}

Affiliations: [a] Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, Jiangsu, China | [b] Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China | [c] Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, USA

Correspondence: [*] Correspondence to: Wei Qian, Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University,Nantong, Jiangsu, China. Tel.: +86 513 85051813; Fax: +86 513 85511585; weiqian@ntu.edu.cn

Correspondence: [*] Correspondence to: Fei Liu, Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA. Tel.: +1 718 494 5263; Fax: +1 718 494 1080; feiliu63@hotmail.com

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

Abstract: Accumulated and abnormally hyperphosphorylated tau aggregates into neurofibrillary tangles in the brains of patients with Alzheimer’s disease (AD). cAMP response binding protein (CREB), a constitutively expressed nuclear transcription factor, is a critical component of the neuroprotective transcriptional network. Numerous studies have shown that cAMP-dependent protein kinase (PKA)-CREB signaling is down-regulated in AD brain. In the present study, we studied the regulation of tau expression by PKA-CREB signaling. We found that the promoter of human tau gene contains three potential cAMP response element (CRE)-like elements, CRE1, CRE2, and CRE3. Overexpression of CREB or activation of PKA significantly suppressed the expression of tau at mRNA and protein levels. ChIP (Chromatin immunoprecipitation) and EMSA (electrophoretic mobility shift assay) revealed that CREB interacted with these three CRE cis-element and that CRE1, among the three elements, plays the most important role in the suppression of tau expression. Furthermore, upregulation of PKA-CREB signaling suppressed expression of endogenous tau. Collectively, these results suggest that PKA-CREB signaling down-regulates tau expression by reducing tau transcription, which may provide a novel insight into the regulation of tau expression and a molecular mechanism involved in tau pathogenesis in AD.

Keywords: CRE, CREB, PKA, tau, transcriptional regulation

DOI: 10.3233/JAD-142610

Journal: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 239-248, 2015