ABSTRACT
Three decades of research, both in vitro and in vivo, have demonstrated the conformational heterogeneity that is displayed by the amyloid ß peptide (Aß) in Alzheimer's disease (AD). Understanding the distinct properties between Aß conformations and how conformation may impact cellular activity remain open questions, yet still continue to provide new insights into protein misfolding and aggregation. In particular, there is interest in the group of soluble oligomeric prefibrillar Aß species comprising lower molecular weight oligomers up to larger protofibrils. In the current study, a number of strategies were utilized to separate Aß protofibrils and oligomers and show that the smaller Aß oligomers have a much different conformation than Aß protofibrils. The differences were consistent for both Aß40 and Aß42. Protofibrils bound thioflavin T to a greater extent than oligomers, and were highly enriched in ß-sheet secondary structure. Aß oligomers possessed a more open structure with significant solvent exposure of hydrophobic domains as determined by tryptophan fluorescence and bis-ANS binding, respectively. The protofibril-selective antibody AbSL readily discerned conformational differences between protofibrils and oligomers. The more developed structure for Aß protofibrils ultimately proved critical for provoking the release of tumor necrosis factor α from microglial cells. The findings demonstrated a dependency on ß-sheet structure for soluble Aß aggregates to cause a microglial inflammatory response. The Aß aggregation process yields many conformationally-varied species with different levels of ß-structure and exposed hydrophobicity. The conformation elements likely determine biological activity and pathogenicity.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Alzheimer Disease/metabolism , Amyloid beta-Peptides/chemistry , Humans , Hydrophobic and Hydrophilic Interactions , Peptide Fragments/chemistry , Protein Conformation, beta-StrandABSTRACT
INTRODUCTION: Extended-release subcutaneous buprenorphine injection is a relatively new formulation and clinicians are still gaining experience with its use. There is sparse literature available on adverse events. We describe a case of skin necrosis associated with the injection site of extended-release buprenorphine. CASE REPORT: A 35-year-old reported immediate swelling and eventual skin breakdown near his buprenorphine injection site. He was found to have ulceration down to the subcutis with no evidence of infection. The patient followed up with dermatology and underwent debridement of the site. The injection site healed with scar formation. DISCUSSION: Although mild to moderate adverse events related to the injection site have been reported in Phase 3 studies of extended-release buprenorphine injection, this is a rare case of skin necrosis requiring surgical intervention and excision of the depot. CONCLUSIONS: This case highlights the potential complication of skin necrosis after inadvertent dermal of extended-release buprenorphine and reviews proper administration techniques.
