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

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 SOD1G93A mice, and in galectin-3 and -9 mRNAs and proteins in spinal cords of both SOD1G93A 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 SOD1G93A/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 SOD1G93A 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 SOD1G93A/Gal-3+/+ cohorts. In addition, microglial staining, as well as TNF-α, and oxidative injury were increased in SOD1G93A/Gal-3−/− mice compared with SOD1G93A/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.

Spinal but not cortical microglia acquire an atypical phenotype with high VEGF, galectin-3 and osteopontin, and blunted inflammatory responses in ALS rats

“…In a murine ALS model, galectin-3 was primarily upregulated in microglial cells (Lerman et al 2012). In the rat ALS model, we show that galectin-3 mRNA is highly upregulated (4 to 7-fold) in microglia at disease onset in brainstem and spinal cord, and it remained elevated until disease end-stage (Fig 5A).…”

“…Therefore it is possible that upregulated galectin-3 in ALS contributes to increased microglial proliferation and/or phagocytosis. SOD1 G93A /galectin-3 −/− mice show more rapid disease progression with more severe symptoms (Lerman et al 2012). However, since galectin-3 is widely expressed in the CNS by many cell types (including motor neurons), it is difficult to infer what cell type mediates this dramatic effect on disease progression.…”

Impact of traumatic brain injury on sleep structure, electrocorticographic activity and transcriptome in mice

“…Like Ccl3 and Cxcl5, Lgals3, which has a role in inflammation and neurodegenerative diseases (Lerman et al, 2012), was increased by mTBI in the cortex (Table S5), whereas S100a8 was decreased. This last observation, although opposite to findings of induction in S100a8 after ischemia and TBI (Engel et al, 2000;Postler et al, 1997), could suggest upregulation of neuroprotective pathways after brain injury since the absence of S100a8 has been linked to neuroprotection (Ziegler et al, 2009).…”

Amyotrophic Lateral Sclerosis, 2016: existing therapies and the ongoing search for neuroprotection

“…Among other possible biomarker candidates, our analyses have identified Parkin-like protein 65 , different zinc and iron binding proteins 66 , alpha-1a antitrypsin 67, 68 , heat shock protein 1, fetuin-A precursor, transferrin, nebulin-related anchoring protein, transthyretin [67][68][69] , and galectin-3 70 . None are robust enough to act as diagnostic or prognostic markers alone, but, with further work, the approach could contribute to better understanding of biological variability enough to help stratify patients in trials.…”