Ghiso J, Rostagno A, Tomidokoro Y, Lashley T, Bojsen-Møller M, Braendgaard H, Plant G, Holton J, Lal R, Revesz T, Frangione B
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
Brain Pathol. 2006 Jan;16(1):71-9. doi: 10.1111/j.1750-3639.2006.tb00563.x.
Classic arguments sustaining the importance of amyloid in the pathogenesis of dementia are usually centered on amyloid beta (Abeta) and its role in neuronal loss characteristic of Alzheimer disease, the most common form of human cerebral amyloidosis. Two non-Abeta cerebral amyloidoses, familial British and Danish dementias, share many aspects of Alzheimer disease, including the presence of neurofibrillary tangles, parenchymal pre-amyloid and amyloid deposits, cerebral amyloid angiopathy, and a widespread inflammatory response. Both early-onset conditions are linked to specific mutations in the BRI2 gene, causing the generation of longer-than-normal protein products and the release of 2 de novo created peptides ABri and ADan, the main components of amyloid fibrils in these inherited dementias. Although the molecular mechanisms and signal transduction pathways elicited by the amyloid deposits and their relation to cognitive impairment remain to be clarified, new evidence indicates that, independent of the differences in their primary structures, Abeta, ABri, and ADan subunits are able to form morphologically compatible ion-channel-like structures and elicit single ion-channel currents in reconstituted lipid membranes. These findings reaffirm the notion that non-Abeta amyloidosis constitute suitable alternative models to study the role of amyloid deposition in the mechanism of neuronal cell death.
支持淀粉样蛋白在痴呆症发病机制中重要性的经典论点通常集中在β淀粉样蛋白（Aβ）及其在阿尔茨海默病（最常见的人类脑淀粉样变性形式）的神经元丢失中的作用上。两种非Aβ脑淀粉样变性疾病，即家族性英国痴呆症和家族性丹麦痴呆症，具有许多与阿尔茨海默病相同的特征，包括存在神经原纤维缠结、实质淀粉样前体和淀粉样沉积物、脑淀粉样血管病以及广泛的炎症反应。这两种早发性疾病都与BRI2基因的特定突变有关，导致产生比正常更长的蛋白质产物，并释放两种新产生的肽ABri和ADan，它们是这些遗传性痴呆症中淀粉样纤维的主要成分。尽管淀粉样沉积物引发的分子机制和信号转导途径及其与认知障碍的关系仍有待阐明，但新证据表明，尽管Aβ、ABri和ADan亚基的一级结构存在差异，但它们能够形成形态上兼容的离子通道样结构，并在重构脂质膜中引发单离子通道电流。这些发现再次证实了这样一种观点，即非Aβ淀粉样变性构成了研究淀粉样沉积在神经元细胞死亡机制中作用的合适替代模型。
