Endogenous aggregates of amyloidogenic cystatin C variant are removed by THP-1 cells in?vitro and induce differentiation and a proinflammatory response

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• 作者：Gudrun Jonsdottir^a ; ^b ; Indiana Elin Ingolfsdottir^a ; Finnbogi R. Thormodsson^a ; ^c ; Petur Henry Petersen^a ; ^b ; ^phenry@hi.is
• 关键词：Cystatin C ; Amyloid ; THP-1 ; Cerebral Amyloid Angiopathy ; Alzheimer's disease
• 刊名：Neurobiology of Aging
• 出版年：2013
• 出版时间：May, 2013
• 年：2013
• 卷：34
• 期：5
• 页码：1389-1396
• 全文大小：1100 K

文摘

A mutation in the human cystatin C gene leads to familial cerebral amyloid angiopathy. This disease is known as ¡°hereditary cerebral hemorrhage with amyloidosis-Icelandic type¡± or ¡°hereditary cystatin C amyloid angiopathy.¡± The mutant cystatin C protein forms aggregates and amyloid, within the central nervous system almost exclusively in connection with the vascular system. It was not known whether immune cells could remove mutant cystatin C protein aggregates. Ex?vivo mutant cystatin C protein aggregates, both in solution and dried onto a glass surface, induced adhesion to the substrate, differentiated the THP-1 monocyte cell line and led to a proinflammatory response. Aggregates were also taken up by both THP-1 cells and THP-1 derived macrophages. These are the same responses induced by other amyloidogenic protein species, such as amyloid ¦Â protein and amylin, supporting the model of all amyloidogenic proteins being toxic due to common structural motifs. Proinflammatory response induced by the ex?vivo mutant cystatin C protein aggregates suggests that vascular inflammation plays an important role in hereditary cerebral hemorrhage with amyloidosis-Icelandic type. Ex?vivo protein aggregates of cystatin C might better model cellular behavior than in?vitro-generated aggregates or supplement in?vitro material.