Lee Yu-Mi, Park Sun-Hee, Lee Duk-Hee
Department of Preventive Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea.
Alzheimers Dement. 2020 Apr;16(4):696-703. doi: 10.1002/alz.12065. Epub 2020 Feb 24.
The aim of this paper is to propose a new hypothesis for the role of lipophilic chemical mixtures stored in adipose tissue in the development of dementia. Specifically, we present how the dynamics of these chemicals can explain the unexpected findings from the Action for Health in Diabetes (Look AHEAD) study, which failed to show long-term benefits of intentional weight loss on cognition, despite substantial improvements in many known risk factors for dementia. Moreover, we discuss how the role of obesity in the risk of dementia can change depending on the dynamics of these chemicals in adipose tissue.
Human adipose tissue is widely contaminated with various neurotoxic chemicals. Typical examples are persistent organic pollutants (POPs), strong lipophilic chemicals with long half-lives. Both unintentional and intentional weight loss increases the release of POPs from adipocytes into the circulation. As POPs in the blood can easily reach the brain, the intentional weight-loss group of the Look AHEAD study may have experienced an unappreciated and long-term disadvantage on their cognition. Additionally, POPs may be involved in the link between obesity and dementia, as dysfunctional hypertrophic adipocytes enhance the release of POPs from adipocytes to the circulation through uncontrolled lipolysis. In contrast, metabolically healthy obese people may have a low risk of dementia because the safe storage of POPs in adipose tissue would decrease the amount of POPs reaching the brain.
In human studies, there are practical difficulties involved with measuring POPs in the blood, including high costs and complex assays. As the serum concentrations of POPs are continuously affected by weight loss and gain, prospective studies may require serial measurements of POPs. In in-vitro and in-vivo experimental studies, how to simulate the exposure dose, duration, and mixture patterns in humans would be critical.
Even though POPs are direct neurotoxins at a high dosage, low-dose POPs are mitochondrial toxins. Therefore, chronic exposure to low-dose POPs is linked to known key interrelated mechanisms in the pathogenesis of dementia, such as mitochondrial dysfunction and neuroinflammation.
本文旨在提出一个关于储存在脂肪组织中的亲脂性化学混合物在痴呆症发展中作用的新假说。具体而言，我们阐述了这些化学物质的动态变化如何解释糖尿病健康行动（Look AHEAD）研究中那些意外的发现，该研究未能显示出有意减肥对认知功能有长期益处，尽管在许多已知的痴呆症风险因素方面有显著改善。此外，我们讨论了肥胖在痴呆症风险中的作用如何根据这些化学物质在脂肪组织中的动态变化而改变。
人体脂肪组织广泛受到各种神经毒性化学物质的污染。典型例子是持久性有机污染物（POPs），即具有长半衰期的强亲脂性化学物质。无意和有意减肥都会增加持久性有机污染物从脂肪细胞释放到循环系统中的量。由于血液中的持久性有机污染物很容易到达大脑，Look AHEAD研究中的有意减肥组可能在认知方面经历了未被认识到的长期不利影响。此外，持久性有机污染物可能参与肥胖与痴呆症之间的联系，因为功能失调的肥大脂肪细胞通过不受控制的脂肪分解增强了持久性有机污染物从脂肪细胞向循环系统的释放。相比之下，代谢健康的肥胖者患痴呆症的风险可能较低，因为持久性有机污染物在脂肪组织中的安全储存会减少到达大脑的持久性有机污染物的量。
在人体研究中，测量血液中的持久性有机污染物存在实际困难，包括成本高和检测复杂。由于持久性有机污染物的血清浓度不断受到体重减轻和增加的影响，前瞻性研究可能需要对持久性有机污染物进行系列测量。在体外和体内实验研究中，如何模拟人体中的暴露剂量、持续时间和混合模式将至关重要。
尽管高剂量的持久性有机污染物是直接的神经毒素，但低剂量的持久性有机污染物是线粒体毒素。因此，长期暴露于低剂量的持久性有机污染物与痴呆症发病机制中已知的关键相互关联机制有关，如线粒体功能障碍和神经炎症。
