Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.
Mol Neurodegener. 2010 Jan 14;5:2. doi: 10.1186/1750-1326-5-2.
Alzheimer's disease (AD) is associated with deposition of amyloid beta (Abeta) in the brain, which is reflected by low concentration of the Abeta1-42 peptide in the cerebrospinal fluid (CSF). There are at least 15 additional Abeta peptides in human CSF and their relative abundance pattern is thought to reflect the production and degradation of Abeta. Here, we test the hypothesis that AD is characterized by a specific CSF Abeta isoform pattern that is distinct when comparing sporadic AD (SAD) and familial AD (FAD) due to different mechanisms underlying brain amyloid pathology in the two disease groups.
We measured Abeta isoform concentrations in CSF from 18 patients with SAD, 7 carriers of the FAD-associated presenilin 1 (PSEN1) A431E mutation, 17 healthy controls and 6 patients with depression using immunoprecipitation-mass spectrometry. Low CSF levels of Abeta1-42 and high levels of Abeta1-16 distinguished SAD patients and FAD mutation carriers from healthy controls and depressed patients. SAD and FAD were characterized by similar changes in Abeta1-42 and Abeta1-16, but FAD mutation carriers exhibited very low levels of Abeta1-37, Abeta1-38 and Abeta1-39.
SAD patients and PSEN1 A431E mutation carriers are characterized by aberrant CSF Abeta isoform patterns that hold clinically relevant diagnostic information. PSEN1 A431E mutation carriers exhibit low levels of Abeta1-37, Abeta1-38 and Abeta1-39; fragments that are normally produced by gamma-secretase, suggesting that the PSEN1 A431E mutation modulates gamma-secretase cleavage site preference in a disease-promoting manner.
阿尔茨海默病（AD）与脑内淀粉样β（Abeta）沉积有关，这反映在脑脊液（CSF）中 Abeta1-42 肽浓度较低。人类 CSF 中至少还有 15 种额外的 Abeta 肽，它们的相对丰度模式被认为反映了 Abeta 的产生和降解。在这里，我们检验了这样一个假设，即 AD 的特征是一种特定的 CSF Abeta 同工型模式，由于两组疾病中脑淀粉样病理学的潜在机制不同，当比较散发性 AD（SAD）和家族性 AD（FAD）时，这种模式是不同的。
我们使用免疫沉淀-质谱法测量了 18 例 SAD 患者、7 例携带 FAD 相关早老素 1（PSEN1）A431E 突变的携带者、17 名健康对照者和 6 例抑郁症患者的 CSF 中 Abeta 同工型浓度。CSF 中 Abeta1-42 水平较低和 Abeta1-16 水平较高可将 SAD 患者和 FAD 突变携带者与健康对照者和抑郁症患者区分开来。SAD 和 FAD 的 Abeta1-42 和 Abeta1-16 均有类似的变化，但 FAD 突变携带者的 Abeta1-37、Abeta1-38 和 Abeta1-39 水平非常低。
SAD 患者和 PSEN1 A431E 突变携带者的 CSF Abeta 同工型模式异常，具有临床相关的诊断信息。PSEN1 A431E 突变携带者的 Abeta1-37、Abeta1-38 和 Abeta1-39 水平较低；这些片段通常是由 γ-分泌酶产生的，这表明 PSEN1 A431E 突变以促进疾病的方式调节 γ-分泌酶切割位点的偏好。
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