簇集蛋白在淀粉样β相关神经退行性变中的作用。
The role of clusterin in amyloid-β-associated neurodegeneration.
机构信息
Department of Radiology, University of California, San Diego, La Jolla.
Department of Psychiatry, University of California, San Diego, La Jolla.
出版信息
JAMA Neurol. 2014 Feb;71(2):180-7. doi: 10.1001/jamaneurol.2013.4560.
IMPORTANCE
Converging evidence indicates that clusterin, a chaperone glycoprotein, influences Alzheimer disease neurodegeneration. However, the precise role of clusterin in Alzheimer disease pathogenesis is still not well understood.
OBJECTIVE
To elucidate the relationship between clusterin, amyloid-β (Aβ), phosphorylated tau (p-tau), and the rate of brain atrophy over time among nondemented older individuals.
DESIGN, SETTING, AND PARTICIPANTS: This longitudinal cohort included cognitively normal older participants and individuals with mild cognitive impairment assessed with baseline lumbar puncture and longitudinal structural magnetic resonance imaging. We examined 241 nondemented older individuals from research centers across the United States and Canada (91 participants with a Clinical Dementia Rating score of 0 and 150 individuals with a Clinical Dementia Rating score of 0.5).
MAIN OUTCOMES AND MEASURES
Using linear mixed-effects models, we investigated interactions between cerebrospinal fluid (CSF) clusterin, CSF Aβ1-42, and CSF p-tau at threonine 181 (p-tau181p) on the atrophy rate of the entorhinal cortex and hippocampus.
RESULTS
Across all participants, we found a significant interaction between CSF clusterin and CSF Aβ1-42 on the entorhinal cortex atrophy rate but not on the hippocampal atrophy rate. Cerebrospinal fluid clusterin was associated with the entorhinal cortex atrophy rate among CSF Aβ1-42-positive individuals but not among CSF Aβ1-42-negative individuals. In secondary analyses, we found significant interactions between CSF Aβ1-42 and CSF clusterin, as well as CSF Aβ1-42 and CSF p-tau181p, on the entorhinal cortex atrophy rate. We found similar results in subgroup analyses within the mild cognitive impairment and cognitively normal cohorts.
CONCLUSIONS AND RELEVANCE
In nondemented older individuals, Aβ-associated volume loss occurs in the presence of elevated clusterin. The effect of clusterin on Aβ-associated brain atrophy is not confounded or explained by p-tau. These findings implicate a potentially important role for clusterin in the earliest stages of the Alzheimer disease neurodegenerative process and suggest independent effects of clusterin and p-tau on Aβ-associated volume loss.
重要性
越来越多的证据表明，伴侣蛋白聚糖（clusterin）作为一种分子伴侣糖蛋白，影响阿尔茨海默病的神经退行性变。然而，伴侣蛋白聚糖在阿尔茨海默病发病机制中的确切作用仍未得到很好的理解。
目的
阐明伴侣蛋白聚糖与淀粉样β（amyloid-β，Aβ）、磷酸化 tau（phosphorylated tau，p-tau）以及无痴呆老年人随时间大脑萎缩率之间的关系。
设计、地点和参与者：本纵向队列研究纳入了认知正常的老年人和伴有轻度认知障碍的个体，他们在基线时进行了腰椎穿刺和纵向结构磁共振成像检查。我们研究了来自美国和加拿大各地研究中心的 241 名无痴呆的老年人（91 名临床痴呆评定量表评分为 0 分，150 名临床痴呆评定量表评分为 0.5 分）。
主要结局和测量指标
采用线性混合效应模型，我们研究了脑脊液（cerebrospinal fluid，CSF）中伴侣蛋白聚糖、CSF Aβ1-42 和 CSF p-tau181p 之间的相互作用对内侧颞叶萎缩率（包括海马体和内嗅皮层）的影响。
结果
在所有参与者中，我们发现 CSF 伴侣蛋白聚糖与 CSF Aβ1-42 之间存在显著的交互作用，与海马体萎缩率无关，而与内嗅皮层萎缩率有关。在 CSF Aβ1-42 阳性个体中，CSF 伴侣蛋白聚糖与内嗅皮层萎缩率有关，但在 CSF Aβ1-42 阴性个体中则没有。在二次分析中，我们发现 CSF Aβ1-42 与 CSF 伴侣蛋白聚糖以及 CSF Aβ1-42 与 CSF p-tau181p 之间存在显著的相互作用，这些交互作用与内嗅皮层萎缩率有关。在轻度认知障碍和认知正常队列的亚组分析中，我们也得到了相似的结果。
结论和相关性
在无痴呆的老年人中，在 Aβ 相关的体积损失存在的情况下，伴侣蛋白聚糖水平升高。伴侣蛋白聚糖对 Aβ 相关脑萎缩的影响不受 p-tau 的影响或干扰。这些发现提示伴侣蛋白聚糖在阿尔茨海默病神经退行性变的早期阶段可能发挥着重要作用，并表明伴侣蛋白聚糖和 p-tau 对 Aβ 相关体积损失的影响是独立的。
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