Up-regulation of the extracellular matrix remodeling genes, biglycan, neutrophil gelatinase-associated lipocalin and matrix metalloproteinase-9 in familial amyloid polyneuropathy

Familial amyloid polyneuropathy (FAP) is characterized by extracellular deposition of transthyretin (TTR) aggregates and amyloid fibrils, particularly in the peripheral nervous system (PNS) and is accompanied with changes in connective tissue. Given the invasiveness of nerve biopsy, FAP salivary glands (SGs) were used in microarray analysis; biglycan and neutrophil gelatinase-associated lipocalin (NGAL), two genes related to extracellular matrix (ECM) remodeling were overexpressed in FAP. Results were validated by RT-PCR and immunohistochemistry both in SG and in nerve biopsies of different stages of disease progression. Matrix metalloproteinase-9 (MMP-9), which exists as a complex with NGAL, was also increased in FAP and in vitro degraded TTR aggregates and fibrils; however in the presence of serum amyloid P, a universal amyloid component, TTR fibrils became resistant to MMP-9 proteolysis. Biglycan, NGAL, and MMP-9 are transcriptionally up-regulated by NF-kB, a transcription factor that is activated in FAP nerves and SG. Given the relationship between inflammation and ECM remodeling, and the increase of proinflammatory cytokines in FAP, IL-10 expression in FAP nerves was investigated; IL-10 increased after fibril deposition, suggesting a balance between proinflammatory and anti-inflammatory mechanisms. Changes in ECM-related proteins and inflammatory events may be relevant for therapy in FAP and other neurodegenerative disorders.