Deletion of galectin‐3 exacerbates microglial activation and accelerates disease progression and demise in a SOD1 G93A mouse model of amyotrophic lateral sclerosis

Brain and Behavior

Bruce J. Lerman³  Eric P. Hoffman⁴  Margaret L. Sutherland¹  Khaled Bouri²  Daniel K. Hsu⁵  Fu-Tong Liu⁵  Jeffrey D. Rothstein⁶ 

[1] NINDS, Neurodegeneration Cluster, National Institutes of Health, Rockville, Maryland;Department of Pediatrics and Center for Genetic Medicine, Children's National Medical Center, Washington, DC;Department of Pharmacology, George Washington University School of Medicine and Health Sciences, Washington, DC;Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC;Department of Dermatology, University of California Davis School of Medicine, Sacramento, California;Department of Neurology, Johns Hopkins University, Baltimore, Maryland

关键词: Alternative activation;    amyotrophic lateral sclerosis;    microglia;    motor neuron disease;    SOD1;   

DOI  :  10.1002/brb3.75

来源: Wiley

【 摘 要 】

Abstract

Galectins are pleiotropic carbohydrate-binding lectins involved in inflammation, growth/differentiation, and tissue remodeling. The functional role of galectins in amyotrophic lateral sclerosis (ALS) is unknown. Expression studies revealed increases in galectin-1 mRNA and protein in spinal cords from SOD1 ^G93A mice, and in galectin-3 and -9 mRNAs and proteins in spinal cords of both SOD1 ^G93A mice and sporadic ALS patients. As the increase in galectin-3 appeared in early presymptomatic stages and increased progressively through to end stage of disease in the mouse, it was selected for additional study, where it was found to be mainly expressed by microglia. Galectin-3 antagonists are not selective and do not readily cross the blood–brain barrier; therefore, we generated SOD1 ^G93A/Gal-3 ^−/− transgenic mice to evaluate galectin-3 deletion in a widely used mouse model of ALS. Disease progression, neurological symptoms, survival, and inflammation were assessed to determine the effect of galectin-3 deletion on the SOD1 ^G93A disease phenotype. Galectin-3 deletion did not change disease onset, but resulted in more rapid progression through functionally defined disease stages, more severely impaired neurological symptoms at all stages of disease, and expiration, on average, 25 days earlier than SOD1 ^G93A/Gal-3 ^+/+ cohorts. In addition, microglial staining, as well as TNF-α, and oxidative injury were increased in SOD1 ^G93A/Gal-3 ^−/− mice compared with SOD1 ^G93A/Gal-3 ^+/+ cohorts. These data support an important functional role for microglial galectin-3 in neuroinflammation during chronic neurodegenerative disease. We suggest that elevations in galectin-3 by microglia as disease progresses may represent a protective, anti-inflammatory innate immune response to chronic motor neuron degeneration.

【 授权许可】

CC BY-NC   
© 2012 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.

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