Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Children's Hospital Oakland Research Institute and University of California San Francisco, San Francisco, CA, USA.
J Alzheimers Dis. 2019;68(3):983-990. doi: 10.3233/JAD-181252.
Cerebral beta-amyloidosis (CA) is a condition in which amyloid-β (Aβ) proteins are deposited in the cerebral cortex and is a predictor of Alzheimer's disease (AD). The Aging Brain Study (ABS) investigated risk factors for CA in persons with diabetes and dyslipidemia. In the ABS, we identified that greater levels of LDL cholesterol and lower levels of HDL cholesterol were associated with increased CA. LDL particles comprise multiple species of varying size, density, and protein composition. For example, within a lipoprotein profile characteristic for persons with obesity and diabetic dyslipidemia, larger LDL particles have a greater ApoE to ApoB ratio, enhancing their binding affinity to LDL receptors. The goal of this study was to identify LDL particles that associate with CA in ABS. LDL particle size fractions were measured by ion mobility in plasma samples of 58 participants (40 women and 18 men). CA was assessed using Pittsburgh Compound B index-Positron Emission Tomography (PiB-PET) imaging. Among the LDL subfractions, greater plasma levels of large LDL particles were significantly associated with greater cerebral amyloidosis and lower hippocampal volumes independent of LDL cholesterol or triglyceride levels. Since Aβ is cleared by the LDL receptor family, such as lipoprotein-like receptor 1 (LRP1), one potential mechanism for our findings is competition between ApoE enriched larger LDL particles and brain-derived Aβ on hepatic Aβ clearance and degradation. We conclude that assessing larger LDL particles in persons with atherogenic dyslipidemia may provide a mechanistic biomarker for the extent of CA.
脑β-淀粉样蛋白（CA）是一种淀粉样β（Aβ）蛋白在大脑皮层中沉积的疾病，是阿尔茨海默病（AD）的预测因子。衰老大脑研究（ABS）研究了糖尿病和血脂异常患者中 CA 的危险因素。在 ABS 中，我们发现 LDL 胆固醇水平较高和 HDL 胆固醇水平较低与 CA 增加有关。LDL 颗粒由多种大小、密度和蛋白组成不同的物种组成。例如，在肥胖和糖尿病血脂异常患者的脂蛋白特征中，较大的 LDL 颗粒具有更大的 ApoE 与 ApoB 比值，增强了它们与 LDL 受体的结合亲和力。本研究的目的是确定与 ABS 中 CA 相关的 LDL 颗粒。通过等离子体样本中的离子迁移率测量 58 名参与者（40 名女性和 18 名男性）的 LDL 颗粒大小分数。使用 Pittsburgh 化合物 B 指数正电子发射断层扫描（PiB-PET）成像评估 CA。在 LDL 亚组分中，较大的血浆大 LDL 颗粒水平与更大的脑淀粉样蛋白和海马体积降低独立于 LDL 胆固醇或甘油三酯水平显著相关。由于 Aβ 被 LDL 受体家族（如脂蛋白样受体 1（LRP1））清除，因此我们研究结果的一个潜在机制是富含 ApoE 的较大 LDL 颗粒与脑源性 Aβ 之间在肝脏 Aβ 清除和降解方面的竞争。我们得出结论，在动脉粥样硬化性血脂异常患者中评估较大的 LDL 颗粒可能为 CA 的程度提供一种机制生物标志物。
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