From the Clinical Memory Research Unit, The Wallenberg Laboratory, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden (NS, LM, MW); and Department of Neuroscience, Mayo Clinic, Jacksonville, Florida (HMN).
J Neuropathol Exp Neurol. 2014 Jul;73(7):684-92. doi: 10.1097/NEN.0000000000000084.
Deposition of amyloid-β (Aβ) 1-42, the major component of senile plaques characteristic of Alzheimer disease, affects brain microvascular integrity and causes blood-brain barrier dysfunction, increased angiogenesis, and pericyte degeneration. To understand the cellular events underlying Aβ1-42 effects on microvascular alterations, we investigated whether different aggregation forms of Aβ1-42 affect shedding of the pericyte proteoglycan NG2 and whether they affect proteolytic cleavage mediated by matrix metalloproteinase (MMP)-9. We found decreased levels of soluble NG2, total MMP-9, and MMP-9 activity in pericyte culture supernatants in response to fibril-enriched preparations of Aβ1-42. Conversely, oligomer-enriched preparations of Aβ1-42 increased soluble NG2 levels in the supernatants. This increase was ablated by the MMP-9/MMP-2 inhibitor SB-3CT. There was also a trend toward increased MMP-9 activity observed after oligomeric Aβ1-42 exposure. Our results, demonstrating an Aβ1-42 aggregation-dependent effect on levels of NG2 and MMP-9, support previous studies showing an impact of Aβ1-42 on vascular integrity and thereby add to our understanding of mechanisms behind the microvascular changes commonly found in patients with Alzheimer disease.
淀粉样蛋白-β (Aβ) 1-42 的沉积是阿尔茨海默病特征性老年斑的主要成分，它影响脑微血管的完整性，导致血脑屏障功能障碍、血管生成增加和周细胞退化。为了了解 Aβ1-42 对微血管改变的细胞事件的影响，我们研究了 Aβ1-42 的不同聚集形式是否影响周细胞蛋白聚糖 NG2 的脱落，以及它们是否影响基质金属蛋白酶 (MMP)-9 介导的蛋白水解切割。我们发现，纤维状 Aβ1-42 富集制剂会降低周细胞培养上清液中可溶性 NG2、总 MMP-9 和 MMP-9 活性的水平。相反，富含寡聚体的 Aβ1-42 会增加上清液中可溶性 NG2 的水平。MMP-9/MMP-2 抑制剂 SB-3CT 可消除这种增加。寡聚 Aβ1-42 暴露后，MMP-9 活性也有增加的趋势。我们的研究结果表明，Aβ1-42 的聚集依赖性对 NG2 和 MMP-9 水平有影响，支持了先前的研究结果，表明 Aβ1-42 对血管完整性有影响，从而进一步了解了在阿尔茨海默病患者中常见的微血管变化背后的机制。
