Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden,
Neuromolecular Med. 2014 Jun;16(2):510-6. doi: 10.1007/s12017-014-8302-1. Epub 2014 Apr 18.
Down's syndrome (DS) patients develop early Alzheimer's disease pathology with abundant cortical amyloid plaques, likely due to overproduction of the amyloid precursor protein (APP), which subsequently leads to amyloid β (Aβ) aggregation. This is reflected in cerebrospinal fluid (CSF) levels of the 42-amino acid long Aβ peptide (Aβ1-42), which are increased in young DS patients and decreases with age. However, it is unclear whether DS also affects other aspects of Aβ metabolism, including production of shorter C- and N-terminal truncated Aβ peptides, and production of peptides from the amyloid precursor-like protein 1 (APLP1), which is related to APP, and cleaved by the same enzymatic processing machinery. APLP1-derived peptides may be surrogate markers for Aβ1-42 production in the brain. Here, we used hybrid immunoaffinity-mass spectrometry and enzyme-linked immunosorbent assays to monitor several Aβ and APLP1 peptides in CSF from DS patients (n = 12) and healthy controls (n = 20). CSF levels of Aβ1-42 and three endogenous peptides derived from APLP1 (APL1β25, APL1β27 and APL1β28) were decreased in DS compared with controls, while a specific Aβ peptide, Aβ1-28, was increased in a majority of the DS individuals. This study indicates that DS causes previously unknown specific alterations of APP and APLP1 metabolism.
唐氏综合征（DS）患者出现大量皮质淀粉样斑块，早期就会发展为阿尔茨海默病病理，这可能是由于淀粉样前体蛋白（APP）过度产生，随后导致淀粉样β（Aβ）聚集。这反映在脑脊液（CSF）中 42 个氨基酸长的 Aβ肽（Aβ1-42）的水平上，在年轻的 DS 患者中增加，并随着年龄的增长而降低。然而，目前尚不清楚 DS 是否还会影响 Aβ代谢的其他方面，包括产生较短的 C-和 N-末端截断的 Aβ肽，以及由淀粉样前体样蛋白 1（APLP1）产生的肽，APLP1 与 APP 相关，并通过相同的酶切加工机制进行切割。APLP1 衍生的肽可能是大脑中 Aβ1-42 产生的替代标志物。在这里，我们使用混合免疫亲和质谱法和酶联免疫吸附测定法来监测来自 DS 患者（n = 12）和健康对照组（n = 20）的 CSF 中的几种 Aβ 和 APLP1 肽。与对照组相比，DS 患者的 CSF 中 Aβ1-42 和源自 APLP1 的三种内源性肽（APL1β25、APL1β27 和 APL1β28）水平降低，而大多数 DS 个体中的特定 Aβ 肽 Aβ1-28 增加。这项研究表明，DS 导致 APP 和 APLP1 代谢的先前未知的特定改变。
