Subcutaneous Administration of Liraglutide Ameliorates Alzheimer-Associated Tau Hyperphosphorylation in Rats with Type 2 Diabetes¹

Issue title: Tau and Beyond for Alzheimer's Disease: A Special Issue dedicated to Dr. Inge Grundke-Iqbal

Guest editors: Alejandra Alonso and Chengxin Gong

Article type: Research Article

Authors: Yang, Yan^a | Zhang, Jing^a | Ma, Delin^a | Zhang, Muxun^a | Hu, Shuhong^a | Shao, Shiying^a | Gong, Cheng-Xin^{b; *}

Affiliations: [a] Department of Endocrinology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China | [b] Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, USA

Correspondence: [*] Correspondence to: Shiying Shao, Department of Endocrinology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China. E-mail: shaoshiying@hotmail.com; Cheng-Xin Gong, Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA. E-mail: chengxin.gong@csi.cuny.edu.

Note: [1] This paper is dedicated to late Inge Grundke-Iqbal, Ph.D., who made seminal contributions to our understanding of neurofibrillary degeneration in Alzheimer’s disease.

Abstract: Background/Objective:Type 2 diabetes increases the risk for developing Alzheimer’s disease (AD), a progressive neurodegenerative disorder. Brain insulin resistance contributes to the pathogenesis of AD, and abnormal hyperphosphorylation of tau protein is crucial to neurodegeneration. Here we studied whether liraglutide, an agonist of glucagon-like peptide-1 (GLP-1) and a new anti-diabetic drug, can promote brain insulin signaling and inhibit tau hyperphosphorylation in the brains of type 2 diabetic rats. Methods:Type 2 diabetic rats were treated with subcutaneous administration of liraglutide (0.2 mg/kg body weight) or, as a control, saline twice a day for up to four weeks. Blood, cerebrospinal fluid (CSF), and brain tissue (n = 7 each group) were collected for analyses after liraglutide or saline administration for one, two, three, and four weeks. Results:We found decreased CSF insulin, hyperphosphorylation of tau at AD-relevant phosphorylation sites, and decreased phosphorylation of protein kinase B (AKT) and glycogen synthase kinase-3β (GSK-3β) in the brain, which indicated decreased insulin signaling leading to overactivation of GSK-3β, a major tau kinase, in type 2 diabetic rats. Liraglutide treatment not only ameliorated hyperglycemia and peripheral insulin resistance, but also reversed these brain abnormalities in a time-dependent manner. Conclusion:Our results indicated that subcutaneous administration of liraglutide restores both peripheral and brain insulin sensitivity and ameliorates tau hyperphosphorylation in rats with type 2 diabetes. These findings support the potential use of liraglutide for the prevention and treatment of AD in individuals with type 2 diabetes.

Keywords: Alzheimer's disease, AKT, GLP-1 agonist, GSK-3β, insulin, liraglutide, tau phosphorylation, type 2 diabetes

DOI: 10.3233/JAD-130491

Journal: Journal of Alzheimer's Disease, vol. 37, no. 3, pp. 637-648, 2013