Agmatine ameliorates type 2 diabetes induced-Alzheimer's disease-like alterations in high-fat diet-fed mice via reactivation of blunted insulin signalling.
The risk of Alzheimer's disease (AD) is higher in patients with type 2 diabetes mellitus (T2DM). Previous studies in high-fat diet-induced AD animal models have shown that brain insulin resistance in these animals leads to the accumulation of amyloid beta (Aβ) and the reduction in GSK-3β phosphorylation, which promotes tau phosphorylation to cause AD. No therapeutic treatments that target AD in T2DM patients have yet been discovered. Agmatine, a primary amine derived from l-arginine, has exhibited anti-diabetic effects in diabetic animals. The aim of this study was to investigate the ability of agmatine to treat AD induced by brain insulin resistance. ICR mice were fed a 60% high-fat diet for 12 weeks and received one injection of streptozotocin (100 mg/kg/ip) 4 weeks into the diet. After the 12-week diet, the mice were treated with agmatine (100 mg/kg/ip) for 2 weeks. Behaviour tests were conducted prior to sacrifice. Brain expression levels of the insulin signal molecules p-IRS-1, p-Akt, and p-GSK-3β and the accumulation of Aβ and p-tau were evaluated. Agmatine administration rescued the reduction in insulin signalling, which in turn reduced the accumulation of Aβ and p-tau in the brain. Furthermore, agmatine treatment also reduced cognitive decline. Agmatine attenuated the occurrence of AD in T2DM mice via the activation of the blunted insulin signal.
Department of Anatomy, Yonsei University College of Medicine, Seoul, 120-752, South Korea; BK21 Plus Project for Medical Sciences, and Brain Research Institute, Yonsei University College of Medicine, Seoul, 120-752, South Korea.
Somang
S
Kang
Department of Pharmacology, Yonsei University College of Medicine, Seoul, 120-752, South Korea.
Chul-Hoon
CH
Kim
Department of Anatomy, Yonsei University College of Medicine, Seoul, 120-752, South Korea; BK21 Plus Project for Medical Sciences, and Brain Research Institute, Yonsei University College of Medicine, Seoul, 120-752, South Korea.
Hosung
H
Jung
Department of Psychiatry, Yonsei University College of Medicine, Seoul, 120-752, South Korea.
Eosu
E
Kim
Department of Diagnostic Radiology, Yonsei University College of Medicine, Seoul, 120-752, South Korea.
Ho-Taek
HT
Song
Department of Anatomy, Yonsei University College of Medicine, Seoul, 120-752, South Korea; BK21 Plus Project for Medical Sciences, and Brain Research Institute, Yonsei University College of Medicine, Seoul, 120-752, South Korea. Electronic address: jelee@yuhs.ac.
Jong Eun
JE
Lee
D000376:Agmatine / Q000494:pharmacology / Q000627:therapeutic use*; D000544:Alzheimer Disease / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D059305:Diet, High-Fat / Q000009:adverse effects*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008813:Mice, Inbred ICR; D011897:Random Allocation
D001786:Blood Glucose; D007328:Insulin; D000376:Agmatine
Agmatine; Alzheimer's disease; Brain insulin resistance; High-fat diet