Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
Instituto de Salud Carlos III, 28029 Madrid, Spain; Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain; Alzheimer's Center Reina Sofia Foundation - CIEN Foundation, 28031 Madrid, Spain.
Neurobiol Dis. 2021 Oct;158:105452. doi: 10.1016/j.nbd.2021.105452. Epub 2021 Jul 21.
Familial British and Danish dementias (FBD and FDD) share striking neuropathological similarities with Alzheimer's disease (AD), including intraneuronal neurofibrillary tangles as well as parenchymal and vascular amyloid deposits. Multiple amyloid associated proteins with still controversial role in amyloidogenesis colocalize with the structurally different amyloid peptides ABri in FBD, ADan in FDD, and Aβ in AD. Genetic variants and plasma levels of one of these associated proteins, clusterin, have been identified as risk factors for AD. Clusterin is known to bind soluble Aβ in biological fluids, facilitate its brain clearance, and prevent its aggregation. The current work identifies clusterin as the major ABri- and ADan-binding protein and provides insight into the biochemical mechanisms leading to the association of clusterin with ABri and ADan deposits. Mirroring findings in AD, the studies corroborate clusterin co-localization with cerebral parenchymal and vascular amyloid deposits in both disorders. Ligand affinity chromatography with downstream Western blot and amino acid sequence analyses unequivocally identified clusterin as the major ABri- and ADan-binding plasma protein. ELISA highlighted a specific saturable binding of clusterin to ABri and ADan with low nanomolar Kd values within the same range as those previously demonstrated for the clusterin-Aβ interaction. Consistent with its chaperone activity, thioflavin T binding assays clearly showed a modulatory effect of clusterin on ABri and ADan aggregation/fibrillization properties. Our findings, together with the known multifunctional activity of clusterin and its modulatory activity on the complex cellular pathways leading to oxidative stress, mitochondrial dysfunction, and the induction of cell death mechanisms - all known pathogenic features of these protein folding disorders - suggests the likelihood of a more complex role and a translational potential for the apolipoprotein in the amelioration/prevention of these pathogenic mechanisms.
家族性英国和丹麦痴呆症（FBD 和 FDD）与阿尔茨海默病（AD）具有惊人的神经病理学相似性，包括神经元内神经原纤维缠结以及实质和血管淀粉样沉积。多种淀粉样相关蛋白在淀粉样生成中仍具有争议性的作用，与 FBD 中的 ABri、FDD 中的 ADan 和 AD 中的 Aβ 共定位。遗传变异和一种相关蛋白（即凝聚素）的血浆水平已被确定为 AD 的风险因素。已知凝聚素可结合生物体液中的可溶性 Aβ，促进其大脑清除，并防止其聚集。目前的研究将凝聚素鉴定为 ABri 和 ADan 的主要结合蛋白，并深入了解导致凝聚素与 ABri 和 ADan 沉积相关的生化机制。与 AD 的研究结果相呼应，这些研究证实了凝聚素在两种疾病中与脑实质和血管淀粉样沉积的共定位。配体亲和层析结合下游 Western blot 和氨基酸序列分析明确鉴定出凝聚素为 ABri 和 ADan 的主要结合血浆蛋白。ELISA 突出显示凝聚素与 ABri 和 ADan 的特异性饱和结合，其 Kd 值在低纳摩尔范围内，与先前证明的凝聚素-Aβ 相互作用的范围相同。与它的伴侣活性一致，硫黄素 T 结合测定清楚地显示凝聚素对 ABri 和 ADan 聚集/纤维化特性的调节作用。我们的研究结果，加上凝聚素的已知多功能活性及其对导致氧化应激、线粒体功能障碍和细胞死亡机制诱导的复杂细胞途径的调节活性——所有这些都是这些蛋白折叠疾病的已知致病特征——表明该载脂蛋白在改善/预防这些致病机制方面可能具有更复杂的作用和转化潜力。
