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 phosph...

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Published in:Neuropharmacology 2017-02, Vol.113 (Pt A), p.467-479
Main Authors: Kang, Somang, Kim, Chul-Hoon, Jung, Hosung, Kim, Eosu, Song, Ho-Taek, Lee, Jong Eun
Format: Article
Language:English
Subjects:
Agmatine
Agmatine - pharmacology
Agmatine - therapeutic use
Alzheimer Disease - blood
Alzheimer Disease - drug therapy
Alzheimer Disease - etiology
Alzheimer's disease
Animals
Blood Glucose - drug effects
Blood Glucose - metabolism
Brain - drug effects
Brain - metabolism
Brain insulin resistance
Diabetes Mellitus, Type 2 - blood
Diabetes Mellitus, Type 2 - drug therapy
Diabetes Mellitus, Type 2 - etiology
Diet, High-Fat - adverse effects
High-fat diet
Insulin - metabolism
Insulin Resistance - physiology
Male
Maze Learning - physiology
Mice
Mice, Inbred ICR
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Summary: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. •HFD induces both peripheral insulin resistance and neuronal insulin resistance.•HFD evokes Alzheimer's disease like alterations; accumulation of Aβ, p-tau, impairment of cognition.•AGM rescues HFD induced insulin resistance.•AGM retrieves blunted brain insulin signalling and reduces Aβ, p-tau.•AGM improves learning and memory functions in HFD mice.
ISSN:0028-3908
1873-7064
DOI:10.1016/j.neuropharm.2016.10.029