Subcutaneous administration of liraglutide ameliorates Alzheimer-associated tau hyperphosphorylation in rats with type 2 diabetes.
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.


CONCLUSIONS
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.
Department of Endocrinology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Yan
Y
Yang
Jing
J
Zhang
Delin
D
Ma
Muxun
M
Zhang
Shuhong
S
Hu
Shiying
S
Shao
Cheng-Xin
CX
Gong
D000544:Alzheimer Disease / Q000378:metabolism* / Q000517:prevention & control; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000517:prevention & control; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000031:analogs & derivatives*; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007279:Injections, Subcutaneous; D000069450:Liraglutide; D008297:Male; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D016875:tau Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
D007004:Hypoglycemic Agents; C489131:Mapt protein, rat; D016875:tau Proteins; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1