Relationship Between Proteolytically Cleaved Gelsolin and Levels of Amyloid-β Protein in the Brains of Down Syndrome Subjects

Abstract

Gelsolin plays an important role in the fibrillogenesis of amyloid-β (Aβ). It binds to Aβ and inhibits its fibrillization. Gelsolin also gets proteolytically cleaved under apoptotic conditions. We recently reported a correlation between proteolytic product of gelsolin (carboxyl-terminal fragment of gelsolin, gelsolin-CTF) and severity of Alzheimer's disease. In this study, we report that gelsolin is cleaved in the brains of adult individuals (age, 43–63 years) with Down syndrome (DS), and that levels of gelsolin-CTF are significantly increased in the frontal cortex of adult DS subjects as compared to age-matched control subjects. Gelsolin-CTF was not observed in frontal cortex of young DS (age 0.5–23 years) and age-matched control subjects. In addition, the levels of both soluble and total Aβ₄₀ and Aβ₄₂ were significantly increased in the frontal cortex of adult DS patients as compared to age-matched control subjects. A positive relationship was observed between gelsolin-CTF in frontal cortex of DS, and the levels of soluble Aβ₄₀ (r² = 0.7820, p < 0.01) and Aβ₄₂ (r² = 0.8179, p < 0.01). Experiments with recombinant full-length gelsolin and its N-terminal and C-terminal fragments showed that similar to gelsolin, proteolytic fragments of gelsolin can also interact with soluble synthetic Aβ. The post-translational modification of gelsolin proteins may not be essential as these proteins (overexpressed in Escherichia coli) were able to form complexes with Aβ. These results suggest that there may be a relationship between proteolytic cleavage of gelsolin and increased Aβ in the brain. Since soluble non-fibrillar forms of Aβ are neurotoxic, they may be involved in apoptosis and proteolysis of gelsolin.