Orally active adiponectin receptor agonist ameliorates AD pathogenesis by potentiating neuronal insulin sensitivity in APP/PS1 mice
Mayuri Khandelwal1,2*, Kapil Manglani1*, Ashu Bhan Tiku2 and Sarika Gupta1,#
1Molecular Science Laboratory, National Institute of Immunology, New Delhi - 110067, India;
2Radiation and Cancer Therapeutics Lab, School of Life Sciences, Jawaharlal Nehru University, New Delhi - 110067, India
Recently, it has been identified that Type II Diabetes (T2D) is the leading cause of Alzheimer's disease (AD) and hence also considered as Type III Diabetes. Therefore understanding the role of recently discovered anti-diabetic drugs in prevention and treatment of AD could be beneficial approach. Since patients suffering from AD have lower levels of adiponectin in the plasma and adiponectin also have anti-diabetic and anti-inflammatory properties which prompted us to investigate the efficacy of small molecule adiponectin receptor agonist (ARA) in curing AD. We report that multiple alterations caused in the brain due to impaired insulin and AMPK signaling is linked to AD, which can be mechanistically improved by employing ARA. Here, we tested the efficacy of anti-diabetic ARA in neuronal cell based insulin resistant model and in AD mice model, APP/PS1. ARA was found to potentiate insulin sensitivity by increasing phosphorylation of key molecules of adiponectin and insulin signaling pathways such as AMPKα, ACC, AKT (Ser 473), GSK3β. Moreover, ARA significantly improved glucose uptake and GLUT4 translocation in insulin resistant neuronal cells. Oral administration of ARA in APP/PS1 transgenic mice prevented memory impairment in Y maze and water maze task along with improved glucose metabolism and decreased Aβ plaque deposition, the hallmark feature of this model. The inflammatory response was also found to be diminished upon ARA administration as evidenced by microgliosis (GFAP) and astrocytosis (Iba-1) markers. Our results highlights that ARA prevents key neurodegenerative traits of AD pathology, suggesting that ARA could be a novel treatment strategy for AD. Moreover, the convenience of oral administration of ARA makes it more attractive to be used as therapeutics in AD, for which no cure is available till date.
- National Institute of Immunology (core grant).
- Department of Biotechnology, Ministry of Science and Technology, India. (BT/PR5474/MED/30/824/2012)
- DST, Science and Engineering Research Board (SB/WEA-011/2013), India.