Affiliations: [a]
College of Life and Health Sciences, Northeastern University, Shenyang, China | [b]
Health Sciences Institute, China Medical University, Shenyang, China | [c]
Department of Experimental Medical Science, Neuronal Plasticity and Repair Unit, Wallenberg Neuroscience Center, Lund University, Lund, Sweden
Correspondence:
[*]
Correspondence to: Pu Zhao, College of Life and Health Sciences, Northeastern University, Shenyang 110819, P.R. China. Tel.: +86 13352453082; E-mails: zhaopu6687700@mail.neu.edu.cn or zhaopu6687700@163.com and Jia-Yi Li, Health Sciences Institute, China Medical University, Shenyang 110112, P. R. China. Tel.: +86 13274256138; E-mails: lijiayi@cmu.edu.cn or jia-yi.li@med.lu.se.
Note: [1] These authors contributed equally to this work.
Note: [2] Lead contact.
Abstract: Background:Alzheimer’s disease (AD) is a neurodegenerative disorder caused by a complex interplay of various factors. However, a satisfactory cure for AD remains elusive. Pharmacological interventions based on drug targets are considered the most cost-effective therapeutic strategy. Therefore, it is paramount to search potential drug targets and drugs for AD. Objective:We aimed to provide novel targets and drugs for the treatment of AD employing transcriptomic data of AD and normal control brain tissues from a new perspective. Methods:Our study combined the use of a multi-layer perceptron (MLP) with differential expression analysis, variance assessment and molecular docking to screen targets and drugs for AD. Results:We identified the seven differentially expressed genes (DEGs) with the most significant variation (ANKRD39, CPLX1, FABP3, GABBR2, GNG3, PPM1E, and WDR49) in transcriptomic data from AD brain. A newly built MLP was used to confirm the association between the seven DEGs and AD, establishing these DEGs as potential drug targets. Drug databases and molecular docking results indicated that arbaclofen, baclofen, clozapine, arbaclofen placarbil, BML-259, BRD-K72883421, and YC-1 had high affinity for GABBR2, and FABP3 bound with oleic, palmitic, and stearic acids. Arbaclofen and YC-1 activated GABAB receptor through PI3K/AKT and PKA/CREB pathways, respectively, thereby promoting neuronal anti-apoptotic effect and inhibiting p-tau and Aβ formation. Conclusions:This study provided a new strategy for the identification of targets and drugs for the treatment of AD using deep learning. Seven therapeutic targets and ten drugs were selected by using this method, providing new insight for AD treatment.
Keywords: Alzheimer’s disease, drug discovery, drug target, multi-layer
perceptron, transcriptome data
