Barrera-Ocampo Alvaro, Arlt Sönke, Matschke Jakob, Hartmann Ursula, Puig Berta, Ferrer Isidre, Zürbig Petra, Glatzel Markus, Sepulveda-Falla Diego, Jahn Holger
From the Institute of Neuropathology (AB-O, JM, BP, MG, DS-F), Department of Psychiatry and Psychotherapy (SA, HJ), University Medical Center Hamburg-Eppendorf, Hamburg, Germany, Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany (UH), Institute of Neuropathology, Bellvitge University Hospital, CIBERNED, Hospitalet de Llobregat, University of Barcelona, Spain (IF), Mosaiques Diagnostics and Therapeutics AG, Hannover, Germany (PZ), and Department of Pharmaceutical Sciences, Natura Research Group, Faculty of Natural Sciences, ICESI University, Cali, Colombia (AB-O).
From the Institute of Neuropathology (AB-O, JM, BP, MG, DS-F), Department of Psychiatry and Psychotherapy (SA, HJ), University Medical Center Hamburg-Eppendorf, Hamburg, Germany, Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany (UH), Institute of Neuropathology, Bellvitge University Hospital, CIBERNED, Hospitalet de Llobregat, University of Barcelona, Spain (IF), Mosaiques Diagnostics and Therapeutics AG, Hannover, Germany (PZ), and Department of Pharmaceutical Sciences, Natura Research Group, Faculty of Natural Sciences, ICESI University, Cali, Colombia (AB-O)
J Neuropathol Exp Neurol. 2016 Sep;75(9):903-16. doi: 10.1093/jnen/nlw065. Epub 2016 Aug 2.
The mechanisms leading to amyloid-β (Aβ) accumulation in sporadic Alzheimer disease (AD) are unknown but both increased production or impaired clearance likely contribute to aggregation. To understand the potential roles of the extracellular matrix proteoglycan Testican-1 in the pathophysiology of AD, we used samples from AD patients and controls and an in vitro approach. Protein expression analysis showed increased levels of Testican-1 in frontal and temporal cortex of AD patients; histological analysis showed that Testican-1 accumulates and co-aggregates with Aβ plaques in the frontal, temporal and entorhinal cortices of AD patients. Proteomic analysis identified 10 fragments of Testican-1 in cerebrospinal fluid (CSF) from AD patients. HEK293T cells expressing human wild type or mutant Aβ precursor protein (APP) were transfected with Testican-1. The co-expression of both proteins modified the sorting of Testican-1 into the endocytic pathway leading to its transient accumulation in Golgi, which seemed to affect APP processing, as indicated by reduced Aβ40 and Aβ42 levels in APP mutant cells. In conclusion, patient data reflect a clearance impairment that may favor Aβ accumulation in AD brains and our in vitro model supports the notion that the interaction between APP and Testican-1 may be a key step in the production and aggregation of Aβ species.
散发性阿尔茨海默病（AD）中导致β淀粉样蛋白（Aβ）积累的机制尚不清楚，但生成增加或清除受损可能都促成了聚集。为了解细胞外基质蛋白聚糖Testican-1在AD病理生理学中的潜在作用，我们使用了AD患者和对照的样本并采用了体外方法。蛋白质表达分析显示AD患者额叶和颞叶皮质中Testican-1水平升高；组织学分析表明，Testican-1在AD患者的额叶、颞叶和内嗅皮质中积累并与Aβ斑块共聚集。蛋白质组学分析在AD患者的脑脊液（CSF）中鉴定出10个Testican-1片段。用Testican-1转染表达人野生型或突变型Aβ前体蛋白（APP）的HEK293T细胞。两种蛋白的共表达改变了Testican-1进入内吞途径的分选，导致其在高尔基体中短暂积累，这似乎影响了APP的加工，如APP突变细胞中Aβ40和Aβ42水平降低所示。总之，患者数据反映了一种清除障碍，可能有利于AD大脑中Aβ的积累，我们的体外模型支持这样一种观点，即APP与Testican-1之间的相互作用可能是Aβ生成和聚集的关键步骤。
