Abstract：
The brain\'s extracellular matrix (ECM) is assumed to undergo rearrangements in Alzheimer\'s disease (AD). Here, we investigated changes of key components of the hyaluronan-based ECM in independent samples of post-mortem brains (N = 19), cerebrospinal fluids (CSF; N = 70), and RNAseq data (N = 107; from The Aging, Dementia and TBI Study) of AD patients and non-demented controls. Group comparisons and correlation analyses of major ECM components in soluble and synaptosomal fractions from frontal, temporal cortex, and hippocampus of control, low-grade, and high-grade AD brains revealed a reduction in brevican in temporal cortex soluble and frontal cortex synaptosomal fractions in AD. In contrast, neurocan, aggrecan and the link protein HAPLN1 were up-regulated in soluble cortical fractions. In comparison, RNAseq data showed no correlation between aggrecan and brevican expression levels and Braak or CERAD stages, but for hippocampal expression of HAPLN1, neurocan and the brevican-interaction partner tenascin-R negative correlations with Braak stages were detected. CSF levels of brevican and neurocan in patients positively correlated with age, total tau, p-Tau, neurofilament-L and Aβ1-40. Negative correlations were detected with the Aβ ratio and the IgG index. Altogether, our study reveals spatially segregated molecular rearrangements of the ECM in AD brains at RNA or protein levels, which may contribute to the pathogenic process.
摘要：
脑的细胞外基质（ECM）被认为在阿尔茨海默病（AD）中发生重排。这里,我们调查了基于透明质酸的ECM的关键成分在独立样本中的变化（N=19），脑脊液（CSF；N=70），和RNAseq数据(N=107；来自老龄化，AD患者和非痴呆对照的痴呆和TBI研究)。来自额叶的可溶性和突触体部分中主要ECM成分的组比较和相关性分析，颞叶皮层,控制海马体，低档,和高级AD大脑显示AD的颞叶皮层可溶性和额叶皮层突触体部分中的brevican减少。相比之下,Neurocan,聚集蛋白聚糖和连接蛋白HAPLN1在可溶性皮质部分中上调.相比之下,RNAseq数据显示聚集蛋白聚糖和brevican表达水平与Braak或CERAD阶段之间没有相关性，但是对于HAPLN1的海马表达，检测到Neurocan和brevican相互作用伴侣tenascin-R与Braak分期呈负相关。患者的脑脊液brevican和neurocan水平与年龄呈正相关，总tau,p-Tau,神经丝-L和Aβ1-40。与Aβ比值和IgG指数呈负相关。总之,我们的研究揭示了AD大脑中ECM在RNA或蛋白质水平上的空间分离的分子重排，这可能有助于致病过程。
