But, these two important peptides had a half-life of only 2 minutes, and degraded by a dipeptidyl-peptidase IV (DPP-4). This precursor protein was cleaved and amidated to two GLP-1 active forms, GLP-1 (7–37) and GLP-1 (7–36). GLP-1 (1–37) peptide is released as a precursor and processed by prohormone convertases. It is an endogenous hormone released from L-cells of the intestine after meal. GLP-1 binding to GLP-1R, could stimulate insulin secretion from the pancreatic β-cells and reduces glucagon secretion from the α-cells to keep glycemic homeostasis in the condition of hyperglycemia. More studies have found that RAGE is involved in cell proliferation and apoptosis, including neurons. It transports only Aβ in circulation into the brain, but not out of the brain. It is found that RAGE, which is on the blood brain barrier, is an important transporter of Aβ. When the ligand binds to RAGE, the formation and aggregation of Aβ in brain were promoted by stimulating BACE1. Īβ is formed by hydrolysis of its precursor protein (β-APP) by β-site amyloid precursor protein cleaving enzyme 1 (BACE1). Indeed, not only increased AGEs levels, but also soluble RAGE levels were found in the plasma of diabetic patients with mild cognitive impairment in previous study. RAGE is a signal-transducing cell surface receptor and promotes Aβ accumulation, which accumulates during AD development. The effects of AGEs depend on its receptor, RAGE. After cross-linking with AGEs, the nucleation and aggregation of Aβ increased in senile plaques. It was further confirmed that AGEs modified β-amyloid (Aβ) during its formation. Moreover, increased AGEs levels were found in most of the senile plaques in Alzheimer’s disease (AD), even in the diffuse plaques. It is suggested that AGEs mediate cognitive impairment induced by hyperglycemia. Additionally, the ability of spatial learning and memory of mice was also impaired.
In an interesting animal study, AGEs increased in serum, cortex and hippocampus after injection of galactose, glucose and other reducing sugars. It was reported that AGEs are involved in aging and dementia. It is believed that AGEs formed by non-enzymatic reactions play an essential role in various chronic complications of diabetes including cognitive dysfunction. Due to the unclear mechanism of diabetic cognition dysfunction, there is no effective treatment for diabetic patients with cognition impairment.
GLP-1R and RAGE were measured by western blotting.Ĭhronic hyperglycemia is a well-recognized risk factor of cognitive impairment in patients with type 2 diabetes mellitus (T2DM). And then, PC12 cells or HT22 cells with AGEs were treated with liraglutide. Neurons and RAGE in hippocampus were shown by immunofluorescence. Liraglutide was used to remedy diabetic mice. Methods db/db mice and db/m mice were used in this study. Although we did not discover the direct-interaction between RAGE and GLP-1R, elevated RAGE levels induced by AGEs were restored by liraglutide.Ĭonclusion We demonstrated that the cognitive function of diabetic mice was improved by liraglutide via the down-regulation of RAGE. However, liraglutide improved the cell activity damaged by AGEs. Moreover, AGEs up-regulated RAGE in PC12 and HT22 cells. We also found decreased cellular activity in cells with AGEs. However, decreased GLP-1R and increased RAGE were reversed by liraglutide. Additionally, up-regulated RAGE and down-regulated glucagon like peptide-1 (GLP-1R) levels were observed in db/db mice.
Moreover, lower glucagon like peptide-1 (GLP-1) levels in plasma were detected in db/db mice. Results Diabetic mice showed decreased cognitive function. We aim to investigate the effect of liraglutide on cognitive function in diabetic mice. Background and aims Advanced glycation end products (AGEs) and receptor of advanced glycation end products (RAGE), are associated with cognition decline.
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