Amyloid-β Precursor Protein Modulates the Sorting of Testican-1 and Contributes to Its Accumulation in Brain Tissue and Cerebrospinal Fluid from Patients with Alzheimer Disease.
Amyloid-β Precursor Protein Modulates the Sorting of Testican-1 and Contributes to Its Accumulation in Brain Tissue and Cerebrospinal Fluid from Patients with Alzheimer Disease.
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DOI：
10.1093/jnen/nlw065
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发表时间：
2016-09
影响因子：
3.2
通讯作者：
Jahn H
中科院分区：
文献类型：
--
作者：
Barrera-Ocampo A;Arlt S;Matschke J;Hartmann U;Puig B;Ferrer I;Zürbig P;Glatzel M;Sepulveda-Falla D;Jahn H
导致散发性阿尔茨海默病（AD）中淀粉样蛋白-β（Aβ）蓄积的机制尚不清楚，但产生增加或清除受损可能有助于聚集。为了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患者和对照的样本以及体外方法。蛋白表达分析显示AD患者额叶和颞叶皮质中Testican-1水平升高;组织学分析显示AD患者额叶、颞叶和内嗅皮质中Testican-1与Aβ斑块聚集并共聚集。蛋白质组学分析鉴定了AD患者脑脊液（CSF）中的Testican-1的10个片段。用Testican-1转染表达人野生型或突变型Aβ前体蛋白（APP）的HEK 293 T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的瞬时积累，这似乎影响APP加工，如APP突变细胞中Aβ40和Aβ42水平降低所示。总之，患者数据反映了可能有利于AD脑中Aβ蓄积的清除障碍，我们的体外模型支持APP和Testican-1之间的相互作用可能是Aβ物质产生和聚集的关键步骤的观点。
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.
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影响因子：
3.7
作者：
Jahn H;Wittke S;Zürbig P;Raedler TJ;Arlt S;Kellmann M;Mullen W;Eichenlaub M;Mischak H;Wiedemann K
通讯作者：
Wiedemann K
影响因子：
2.9
作者：
Cohlberg, JA;Li, J;Fink, AL
通讯作者：
Fink, AL
影响因子：
82.9
作者：
HAASS, C;LEMERE, CA;SELKOE, DJ
通讯作者：
SELKOE, DJ
影响因子：
4.4
作者：
Charbonnier, F;Périn, JP;Alliel, PM
通讯作者：
Alliel, PM
影响因子：
4.7
作者：
FRASER, PE;NGUYEN, JT;KIRSCHNER, DA
通讯作者：
KIRSCHNER, DA