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.

• Authors: Lina Ji, Ved Chauhan, Pankaj Mehta, Jerzy Wegiel, Sangita Mehta, Abha Chauhan
• Journal: Journal of Alzheimer's disease : JAD (J Alzheimers Dis) Vol. 22 Issue 2 Pg. 609-17 ( 2010) ISSN: 1875-8908 [Electronic] Netherlands
• PMID: 20847428 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Gelsolin
• Peptide Fragments
• amyloid beta-protein (1-40)
• amyloid beta-protein (1-42)
• enhanced green fluorescent protein
• Green Fluorescent Proteins

Topics

• Adolescent
• Adult
• Age Factors
• Amyloid beta-Peptides (metabolism, pharmacology)
• Case-Control Studies
• Child
• Child, Preschool
• Down Syndrome (pathology)
• Enzyme-Linked Immunosorbent Assay (methods)
• Female
• Frontal Lobe (metabolism)
• Gelsolin (genetics, metabolism)
• Green Fluorescent Proteins (genetics)
• Humans
• Immunoprecipitation (methods)
• In Vitro Techniques
• Infant
• Infant, Newborn
• Male
• Middle Aged
• Peptide Fragments (genetics, metabolism, pharmacology)
• Young Adult