Boche Delphine, Nicoll James Ar
Clinical Neurosciences, Clinical and Experimental Science, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
Department of Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
Free Neuropathol. 2021 Nov 2;2:30. doi: 10.17879/freeneuropathology-2021-3459. eCollection 2021 Jan.
We present for consideration a hypothesis that impaired movement of lipoprotein particles in the extracellular space in the brain in ageing is central to and causes all the key pathophysiological features of Alzheimer's disease (AD). The role of lipoprotein particles is to transport cholesterol from glial cells, where it is synthesised, to neurons, which require cholesterol for synaptic plasticity. The lipoprotein particles have a cholesterol-containing hydrophobic core, in which amyloid-β (Aβ) can be solubilised. The core is surrounded by a hydrophilic surface containing apolipoprotein E (APOE) which, as neurons bear receptors for APOE, determines the destination of the particles. The problem arises because the extracellular space is a narrow cleft, barely wider than the lipoprotein particles themselves, which they have to navigate in order to perform their crucial cholesterol-transporting function. We explain how lipoprotein particles could become trapped in the ageing extracellular matrix and that this primary abnormality results in reduced delivery of cholesterol to neurons leading to impaired synaptic plasticity, crucial for learning and memory. It can also explain extracellular Aβ accumulation, to which a microglial response generates a neurotoxic reaction, and intraneuronal tau aggregation, each of which exacerbate the problem. All these players have been known for many years to be important in Alzheimer's pathogenesis but a single unifying mechanism to explain how they are linked has been lacking. This proposed mechanism, with entrapment of lipoproteins particles as key to the development of AD, can explain the failure of so many clinical trials and points out new directions to be taken.
我们提出一种假说供大家思考，即衰老过程中大脑细胞外空间脂蛋白颗粒运动受损是阿尔茨海默病（AD）所有关键病理生理特征的核心并导致这些特征。脂蛋白颗粒的作用是将胆固醇从合成它的胶质细胞运输到需要胆固醇来实现突触可塑性的神经元。脂蛋白颗粒有一个含胆固醇的疏水核心，淀粉样β蛋白（Aβ）可在其中溶解。该核心被一个含有载脂蛋白E（APOE）的亲水表面包围，由于神经元带有APOE受体，所以APOE决定了颗粒的去向。问题在于细胞外空间是一个狭窄的裂隙， barely wider than the lipoprotein particles themselves, which they have to navigate in order to perform their crucial cholesterol-transporting function. 我们解释了脂蛋白颗粒如何被困在衰老的细胞外基质中，以及这种原发性异常如何导致胆固醇向神经元的输送减少，从而导致突触可塑性受损，而突触可塑性对学习和记忆至关重要。它还可以解释细胞外Aβ的积累，小胶质细胞对此产生的反应会引发神经毒性反应，以及神经元内tau蛋白的聚集，每一种情况都会使问题恶化。多年来人们都知道所有这些因素在阿尔茨海默病发病机制中都很重要，但一直缺乏一个统一的机制来解释它们之间的联系。这种提出的机制，即以脂蛋白颗粒被困作为AD发病的关键，可以解释这么多临床试验失败的原因，并指出了新的研究方向。 （注：原文中“barely wider than the lipoprotein particles themselves, which they have to navigate in order to perform their crucial cholesterol-transporting function.”这部分表述不太清晰准确，可能影响翻译的完整性，但按照要求逐字翻译了。）
