Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India.
Cell Mol Neurobiol. 2022 Nov;42(8):2527-2551. doi: 10.1007/s10571-021-01147-7. Epub 2021 Sep 13.
Alzheimer's disease (AD) is an aging-related neurodegenerative disorder. It is characterized clinically by progressive memory loss and impaired cognitive function. Its progression occurs from neuronal synapse loss to amyloid pathology and Tau deposit which eventually leads to the compromised neuronal function. Neurons in central nervous tissue work in a composite and intricate network with the glia and vascular cells. Microglia and astrocytes are becoming the prime focus due to their involvement in various aspects of neurophysiology, such as trophic support to neurons, synaptic modulation, and brain surveillance. AD is also often considered as the sequela of prolonged metabolic dyshomeostasis. The neuron and glia have different metabolic profiles as cytosolic glycolysis and mitochondrial-dependent oxidative phosphorylation (OXPHOS), especially under dyshomeostasis or with aging pertaining to their unique genetic built-up. Various efforts are being put in to decipher the role of mitochondrial dynamics regarding their trafficking, fission/fusion imbalance, and mitophagy spanning over both neurons and glia to improve aging-related brain health. The mitochondrial dysfunction may lead to activation in various signaling mechanisms causing metabolic reprogramming in glia cells, further accelerating AD-related pathogenic events. The glycolytic-dominant astrocytes switch to the neurotoxic phenotype, i.e., disease-associated astrocyte under metabolic stress. The microglia also transform from resting to reactive phenotype, i.e., disease-associated microglia. It may also exist in otherwise a misconception an M1, glycolytic, or M2, an OXPHOS-dependent phenotype. Further, glial transformation plays a vital role in regulating hallmarks of AD pathologies like synapse maintenance, amyloid, and Tau clearance. In this updated review, we have tried to emphasize the metabolic regulation of glial reactivity, mitochondrial quality control mechanisms, and their neuroinflammatory response in Alzheimer's progression.
阿尔茨海默病（AD）是一种与衰老相关的神经退行性疾病。临床上表现为进行性记忆丧失和认知功能障碍。其进展是从神经元突触丧失到淀粉样蛋白病理和 Tau 沉积，最终导致神经元功能受损。中枢神经系统中的神经元与胶质细胞和血管细胞一起形成一个复杂的网络。小胶质细胞和星形胶质细胞因其参与神经生理学的各个方面而成为主要焦点，例如神经元的营养支持、突触调节和大脑监测。AD 也常被认为是长期代谢失衡的后遗症。神经元和胶质细胞具有不同的代谢特征，如细胞质糖酵解和线粒体依赖性氧化磷酸化（OXPHOS），尤其是在代谢失衡或衰老时，这与它们独特的遗传构成有关。人们正在努力阐明线粒体动力学在神经元和胶质细胞中的作用，包括它们的运输、裂变/融合失衡和线粒体自噬，以改善与衰老相关的大脑健康。线粒体功能障碍可能导致各种信号通路的激活，导致胶质细胞的代谢重编程，进一步加速 AD 相关的致病事件。糖酵解占主导地位的星形胶质细胞转变为神经毒性表型，即代谢应激下的疾病相关星形胶质细胞。小胶质细胞也从静止状态转变为反应性表型，即疾病相关的小胶质细胞。它也可能存在于其他误解中，即 M1、糖酵解或 M2，一种依赖 OXPHOS 的表型。此外，胶质细胞的转化在调节 AD 病理的标志性特征方面起着至关重要的作用，如突触维持、淀粉样蛋白和 Tau 的清除。在这篇更新的综述中，我们试图强调胶质细胞反应性的代谢调节、线粒体质量控制机制及其在 AD 进展中的神经炎症反应。
