An impairment of amyloid β-peptide (Aβ) clearance is suggested to play a key role in the pathogenesis of sporadic Alzheimer's disease (AD). Amyloid degradation is mediated by various mechanisms including fragmentation by enzymes like neprilysin, matrix metalloproteinases (MMPs) and a recently identified amyloidolytic activity of β-site amyloid precursor protein cleaving enzyme 1 (BACE1). BACE1 cleavage of Aβ40 and Aβ42 results in the formation of a common Aβ34 intermediate which was found elevated in cerebrospinal fluid levels of patients at the earliest disease stages. To further investigate the role of Aβ34 as a marker for amyloid clearance in AD, we performed a systematic and comprehensive analysis of Aβ34 immunoreactivity in hippocampal and cortical post-mortem brain tissue from AD patients and non-demented elderly individuals. In early Braak stages, Aβ34 was predominantly detectable in a subset of brain capillaries associated with pericytes, while in later disease stages, in clinically diagnosed AD, this pericyte-associated Aβ34 immunoreactivity was largely lost. Aβ34 was also detected in isolated human cortical microvessels associated with brain pericytes and its levels correlated with Aβ40, but not with Aβ42 levels. Moreover, a significantly decreased Aβ34/Aβ40 ratio was observed in microvessels from AD patients in comparison to non-demented controls suggesting a reduced proteolytic degradation of Aβ40 to Aβ34 in AD. In line with the hypothesis that pericytes at the neurovascular unit are major producers of Aβ34, biochemical studies in cultured human primary pericytes revealed a time and dose dependent increase of Aβ34 levels upon treatment with recombinant Aβ40 peptides while Aβ34 production was impaired when Aβ40 uptake was reduced or BACE1 activity was inhibited. Collectively, our findings indicate that Aβ34 is generated by a novel BACE1-mediated Aβ clearance pathway in pericytes of brain capillaries. As amyloid clearance is significantly reduced in AD, impairment of this pathway might be a major driver of the pathogenesis in sporadic AD.

中文翻译：

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淀粉样蛋白-β降解中间产物Aβ34在阿尔茨海默氏病患者的脑毛细血管中与周细胞相关并减少。

淀粉样蛋白β肽（Aβ）清除的损害被认为在散发性阿尔茨海默氏病（AD）的发病机理中起关键作用。淀粉样蛋白的降解是由多种机制介导的，包括诸如中性溶酶，基质金属蛋白酶（MMPs）的酶裂解以及最近发现的β位淀粉样蛋白前体蛋白裂解酶1（BACE1）的淀粉样水解活性。BACE1对Aβ40和Aβ42的切割导致形成常见的Aβ34中间体，发现该中间体在疾病的早期阶段的脑脊液水平升高。为了进一步研究Aβ34作为AD中淀粉样蛋白清除的标志物的作用，我们对AD患者和非痴呆老年人的海马和皮质死后脑组织中的Aβ34免疫反应性进行了系统，全面的分析。在Braak早期，主要在与周细胞相关的脑毛细血管亚群中检测到Aβ34，而在疾病后期，在临床诊断的AD中，这种与周细胞相关的Aβ34免疫反应性大量丧失。在与脑周细胞相关的分离的人皮层微血管中也检测到Aβ34，其水平与Aβ40相关，但与Aβ42水平无关。此外，与非痴呆对照相比，在AD患者的微血管中观察到Aβ34/Aβ40比率显着降低，表明AD中Aβ40至Aβ34的蛋白水解降解降低。符合以下假设：神经血管单元的周细胞是Aβ34的主要产生者，在培养的人类原代周细胞中进行的生化研究表明，重组Aβ40肽处理后，Aβ34水平随时间和剂量的增加而增加，而当Aβ40摄取减少或BACE1活性受到抑制时，Aβ34的产生就会受到损害。总体而言，我们的发现表明Aβ34是由脑毛细血管周细胞中的新型BACE1介导的Aβ清除途径产生的。由于AD中淀粉样蛋白清除率显着降低，因此该途径的损伤可能是散发性AD发病机理的主要驱动因素。