Hoos Michael D, Ahmed Mahiuddin, Smith Steven O, Van Nostrand William E
Department of Medicine, Stony Brook University, Stony Brook, New York 11794-8153, USA.
Biochemistry. 2009 Jun 9;48(22):4720-7. doi: 10.1021/bi900037s.
The deposition of amyloid beta-protein (Abeta) fibrils into plaques within the brain parenchyma and along cerebral blood vessels is a hallmark of Alzheimer's disease. Abeta peptides are produced through the successive cleavage of the Abeta precursor protein by beta- and gamma-secretase, producing peptides between 39 and 43 amino acids in length. The most common of these are Abeta40 (the most abundant) and Abeta42. Abeta42 is more fibrillogenic than Abeta40 and has been implicated in early Abeta plaque deposition. Our previous studies determined that myelin basic protein (MBP) was capable of inhibiting fibril formation of a highly fibrillogenic Abeta peptide containing both E22Q (Dutch) and D23N (Iowa) mutations associated with familial forms of cerebral amyloid angiopathy [Hoos, M. D., et al. (2007) J. Biol. Chem. 282, 9952-9961]. In this study, we show through a combination of biochemical and ultrastructural techniques that MBP is also capable of inhibiting the beta-sheet fibrillar assembly of the normal Abeta42 peptide. These findings suggest that MBP may play a role in regulating the deposition of Abeta42 and thereby also may regulate the early formation of amyloid plaques in Alzheimer's disease.
β-淀粉样蛋白（Aβ）纤维在脑实质内和沿脑血管沉积形成斑块是阿尔茨海默病的一个标志。Aβ肽是通过β-分泌酶和γ-分泌酶对Aβ前体蛋白的连续切割产生的，产生的肽长度在39至43个氨基酸之间。其中最常见的是Aβ40（含量最丰富）和Aβ42。Aβ42比Aβ40更易形成纤维，并且与早期Aβ斑块沉积有关。我们之前的研究确定，髓鞘碱性蛋白（MBP）能够抑制一种高度易形成纤维的Aβ肽的纤维形成，该肽含有与家族性脑淀粉样血管病相关的E22Q（荷兰型）和D23N（爱荷华型）突变[胡斯，医学博士等人（2007年）《生物化学杂志》282卷，9952 - 9961页]。在本研究中，我们通过生物化学和超微结构技术相结合表明，MBP也能够抑制正常Aβ42肽的β-折叠纤维组装。这些发现表明，MBP可能在调节Aβ42的沉积中发挥作用，从而也可能调节阿尔茨海默病中淀粉样斑块的早期形成。
