Modeling of AMPK Regulatory Network in Alzheimer's Disease

Junsheng Wang, Enze Xu, Yang Xiao, Chunrui Xu, Minghan Chen

Abstract: AMP-activated protein kinase (AMPK), a cellular energy sensor in response to changes in the ADP/ATP ratio, has been proven to not only play roles in metabolic actions but also holds pivotal roles in neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease, and Lewy body dementia. However, the downstream effectors regulated by AMPK and its specific contributions to the pathology of these diseases remain elusive. In this study, we combine the power of systems biology and neuroscience to understand the dynamics and regulatory effects of AMPK under the progression of AD. Particularly, our study develops a regulatory protein network that seeks to demystify this intricate protein-protein interaction, placing particular emphasis on the role of AMPK in the pathology of AD. By focusing on two important cellular activities, mRNA translation and autophagy, our model explores the underlying effects of the central governance of a change in AMPK activity and concludes that eEF2-controlled translation is more sensitive to the perturbation. Additionally, we adjust various kinetic parameters to restore proteins affected by the disease to their baseline levels, with the goal of identifying potential new drug targets. The model accurately captures the regulatory effect of AMPK, provides the temporal dynamics of key regulators in AD progression, contributes to the understanding of the disease’s pathophysiology, and potentially generalizes the function of AMPK into other neurodegenerative diseases.