Therapeutic potential of simvastatin in ALS: Enhanced axonal integrity and motor neuron survival through Apoa4 and Alb modulation

Song Luo; Xiaorui Wang; Bo Ma; Dongliang Liu; Li Li; Lijin Wang; Ning Ding; Liangyu Zou; Jie Wang; Jialin Pan; Daoqian Sang; Huadong Zhou; Hongdang Qu; Yi Lu; Lijuan Yang

doi:10.17305/bb.2024.11218

Authors

Song Luo Department of Neurology, the First Affiliated Hospital of Bengbu Medical University, Bengbu, China
Xiaorui Wang Department of Neurology, the First Affiliated Hospital of Bengbu Medical University, Bengbu, China
Bo Ma Department of Neurology, the First Affiliated Hospital of Bengbu Medical University, Bengbu, China
Dongliang Liu Department of Neurology, the First Affiliated Hospital of Bengbu Medical University, Bengbu, China
Li Li Department of Neurology, the First Affiliated Hospital of Bengbu Medical University, Bengbu, China
Lijin Wang Department of Psychiatry, Bengbu Medical University, Bengbu, China
Ning Ding Department of Hematology, the First Affiliated Hospital of Bengbu Medical University, Bengbu, China
Liangyu Zou Department of Neurology, Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan University, Shenzhen, China
Jie Wang International Medical Center (Department of Geriatric Medicine), Shenzhen University General Hospital, Shenzhen, China
Jialin Pan Department of Internal Medicine, Second People’s Hospital, Longgang District, Shenzhen, China
Daoqian Sang Department of Neurology, the First Affiliated Hospital of Bengbu Medical University, Bengbu, China
Huadong Zhou Department of Neurology, the First Affiliated Hospital of Bengbu Medical University, Bengbu, China
Hongdang Qu Department of Neurology, the First Affiliated Hospital of Bengbu Medical University, Bengbu, China
Yi Lu Department of Neurology, the First Affiliated Hospital of Bengbu Medical University, Bengbu, China
Lijuan Yang Department of Pediatrics, the First Affiliated Hospital of Bengbu Medical University, Bengbu, China

DOI:

https://doi.org/10.17305/bb.2024.11218

Keywords:

Simvastatin, amyotrophic lateral sclerosis, transgenic mouse model, Apoa4, Alb

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons in the spinal cord, brainstem, and motor cortex. This study investigates the effects of simvastatin on the G93A-copper/zinc superoxide dismutase (G93ASOD1) transgenic mouse model of ALS. The experiment included three groups: C57BL/6 wild-type mice, C57BL/6J SOD1^G93A mice treated with PBS (SOD1^G93A + PBS), and C57BL/6J SOD1^G93Amice treated with simvastatin (SOD1^G93A + simvastatin). The primary endpoints were survival rates, body weight changes, performance in pole climbing and suspension tests, and neurological deficit scores. Pathological changes were assessed using hematoxylin and eosin staining, transmission electron microscopy, Nissl staining, and Masson staining. Proteomic and metabolomic analyses were performed to identify differentially expressed proteins (DEPs) and metabolites. Quantitative real-time polymerase chain reaction and western blotting were used to measure gene expression. Although there were no significant differences in survival rates, body weight, pole climbing, and suspension test performance, or neurological deficit scores between the SOD1^G93A + simvastatin and SOD1^G93A + PBS groups, simvastatin treatment improved axonal organization within the spinal cord, increased the number of neurons, and reduced cytoplasmic swelling and gastrocnemius fibrosis. A total of 47 DEPs and 13 differential metabolites were identified between the SOD1^G93A+ PBS and SOD1^G93A + simvastatin groups. Notably, the expression levels of Apoa4 and Alb were elevated in the SOD1^G93A + simvastatin group compared to the SOD1^G93A + PBS group. Our results suggest that simvastatin may have potential therapeutic effects in ALS, likely involving the modulation of Apoa4 and Alb expression.