Akyol Omer, Akyol Sumeyya, Chou Mei-Chuan, Chen Shioulan, Liu Ching-Kuan, Selek Salih, Soares Jair C, Chen Chu-Huang
Molecular Cardiology, Vascular and Medicinal Research, The Texas Heart Institute, Houston, TX, United States.
NX Prenatal, Houston, TX, United States.
Front Neurosci. 2023 Nov 16;17:1275932. doi: 10.3389/fnins.2023.1275932. eCollection 2023.
Alzheimer's disease (AD) and other classes of dementia are important public health problems with overwhelming social, physical, and financial effects for patients, society, and their families and caregivers. The pathophysiology of AD is poorly understood despite the extensive number of clinical and experimental studies. The brain's lipid-rich composition is linked to disturbances in lipid homeostasis, often associated with glucose and lipid abnormalities in various neurodegenerative diseases, including AD. Moreover, elevated low-density lipoprotein (LDL) cholesterol levels may be related to a higher probability of AD. Here, we hypothesize that lipids, and electronegative LDL (L5) in particular, may be involved in the pathophysiology of AD. Although changes in cholesterol, triglyceride, LDL, and glucose levels are seen in AD, the cause remains unknown. We believe that L5-the most electronegative subfraction of LDL-may be a crucial factor in understanding the involvement of lipids in AD pathology. LDL and L5 are internalized by cells through different receptors and mechanisms that trigger separate intracellular pathways. One of the receptors involved in L5 internalization, LOX-1, triggers apoptotic pathways. Aging is associated with dysregulation of lipid homeostasis, and it is believed that alterations in lipid metabolism contribute to the pathogenesis of AD. Proposed mechanisms of lipid dysregulation in AD include mitochondrial dysfunction, blood-brain barrier disease, neuronal signaling, inflammation, and oxidative stress, all of which lead ultimately to memory loss through deficiency of synaptic integration. Several lipid species and their receptors have essential functions in AD pathogenesis and may be potential biomarkers.
阿尔茨海默病（AD）和其他类型的痴呆症是重要的公共卫生问题，对患者、社会及其家庭和护理人员产生了巨大的社会、身体和经济影响。尽管进行了大量的临床和实验研究，但AD的病理生理学仍未得到充分理解。大脑富含脂质的成分与脂质稳态紊乱有关，这通常与包括AD在内的各种神经退行性疾病中的葡萄糖和脂质异常有关。此外，低密度脂蛋白（LDL）胆固醇水平升高可能与AD的较高发病概率相关。在此，我们假设脂质，特别是带负电荷的LDL（L5），可能参与AD的病理生理学过程。虽然在AD中可见胆固醇、甘油三酯、LDL和葡萄糖水平的变化，但其原因仍然未知。我们认为，L5（LDL中带负电荷最多的亚组分）可能是理解脂质在AD病理过程中作用的关键因素。LDL和L5通过不同的受体和机制被细胞内化，从而触发不同的细胞内途径。参与L5内化的受体之一，凝集素样氧化低密度脂蛋白受体1（LOX-1），触发细胞凋亡途径。衰老与脂质稳态失调有关，并且人们认为脂质代谢的改变有助于AD的发病机制。AD中脂质失调的提出机制包括线粒体功能障碍、血脑屏障疾病、神经元信号传导、炎症和氧化应激，所有这些最终都通过突触整合缺陷导致记忆丧失。几种脂质种类及其受体在AD发病机制中具有重要功能，可能是潜在的生物标志物。
