Role of adipokines and insulin in the pathogenesis of Alzheimer’s disease: A Clinical- Experimental Study

Vineet Kumar Khemka1,2, Anirban Ganguly1, Anindita Banerjee2, Atanu Biswas3, and Sasanka Chakrabarti 2.

1Institute of Post Graduate Medical Education & Research, Kolkata, India.

2 ICARE Institute of Medical Sciences and Research, Haldia, India.

3 Bangur Institute of Neurosciences, Kolkata, India.

Background: An early metabolic event in Alzheimer’s disease (AD) is decreased cerebral glucose utilization and an altered glucose and energy metabolism is considered to play an important role in the disease pathogenesis. However, the role of different hormones that regulate glucose and lipid metabolism, food intake and hunger in the pathogenesis of AD is not established.

Methods: In this context we measured and compared the serum levels of insulin, adiponectin and leptin in 60 AD patients and 60 age-matched controls. Further, SHSY5Y cells were exposed to Leptin antagonist (200-600 ng/ml) and adiponectin (200-600 ng/ml) for 6h and 48h followed by the measurement of APP gene expression, BACE gene expression, Amyloid beta (Aβ-42) content and β secretase activity as well as cytotoxicity assay and ROS load. Results: In AD subjects, a markedly raised value of serum adiponectin and serum insulin were observed (p <0.001) while a lower level of serum leptin (p <0.001) were noticed. Moreover, our results show that LA causes significant change in APP mRNA expression, increased accumulation of Aβ-42, moderate increase in β secretase activity with enhanced

production of ROS and loss of viability in SHSY5Y cells. However, no change in BACE 1 gene expression was observed.

Conclusions: Our results imply that adipokines and possibly insulin have important contributions in AD pathogenesis presumably through direct actions on CNS leading to metabolic dysregulation in the brain. Further, it can be inferred that a deficient leptin signaling can mimic several key molecular features of AD pathogenesis like APP and amyloid beta metabolism and oxidative stress in SHSY5Y cells and can be a possible target for developing supplementation therapies for reducing the progression of AD.

Funding: This study was supported by the Department of Biotechnology (DBT), NewDelhi, India.