脂联素
内分泌学
胰岛素抵抗
脂联素受体1
神经炎症
内科学
β淀粉样蛋白
安普克
胰岛素受体
胰岛素
生物
医学
细胞生物学
蛋白激酶A
炎症
激酶
疾病
作者
Mayuri Khandelwal,Kapil Manglani,Prabhat Upadhyay,Mohammad Abul Kalam Azad,Sarika Gupta
标识
DOI:10.1016/j.nbd.2022.105876
摘要
Alzheimer's disease (AD) is a progressive devastating neurodegenerative disorder characterized by extracellular amyloid beta (Aβ42) plaque formation, hyperphosphorylation of tau protein leading to intracellular neurofibrillary tangle formation. Recently discovered hallmark features responsible for AD pathogenesis are neuronal insulin resistance, dysregulation in adiponectin and AMPK signaling. The presence of adiponectin and its receptor in the brain with its unique anti-diabetic effects and association with neurodegenerative diseases has raised our interest in exploring orally active small molecule adiponectin receptor agonist, AdipoRon. To date, all the available drugs for the treatment of AD provides symptomatic relief and do not stall the progression of the disease. Indeed, it is becoming increasingly apparent to find appropriate targets. Here, we attempt to shed lights on adiponectin receptor agonist, AdipoRon and its downstream molecular targets in reducing disease pathogenesis and insulin resistance. In brain, AdipoRon induced AMPK activation, increased insulin sensitivity, reduced amyloid beta plaque deposition and improved cognitive impairment. Levels of BACE were also downregulated while LDLR, APOE and neprilysin were upregulated promoting amyloid beta clearance from brain. AdipoRon further reduced the chronic inflammatory marker, GFAP and improved synaptic markers PSD-95 and synaptophysin in APP/PS1 mice. Our in-vitro studies further confirmed the potential role of AdipoRon in improving insulin sensitivity by increasing GLUT 4 translocation, glucose uptake and insulin signaling under hyperinsulinemic condition. Our findings suggest that AdipoRon could be a promising lead in the future treatment strategies in the development of effective AD treatment.
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