Faculty of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8575, Ibaraki, Japan.
Institute for Biomedical Research, MCBI, 4-9-29 Matsushiro, Tsukuba 305-0035, Ibaraki, Japan.
Cells. 2022 Mar 7;11(5):919. doi: 10.3390/cells11050919.
Alzheimer's disease (AD) is a multifactorial disease with a heterogeneous etiology. The pathology of Alzheimer's disease is characterized by amyloid-beta and hyperphosphorylated tau, which are necessary for disease progression. Many clinical trials on disease-modifying drugs for AD have failed to indicate their clinical benefits. Recent advances in fundamental research have indicated that neuroinflammation plays an important pathological role in AD. Damage- and pathogen-associated molecular patterns in the brain induce neuroinflammation and inflammasome activation, causing caspase-1-dependent glial and neuronal cell death. These waste products in the brain are eliminated by the glymphatic system via perivascular spaces, the blood-brain barrier, and the blood-cerebrospinal fluid barrier. Age-related vascular dysfunction is associated with an impairment of clearance and barrier functions, leading to neuroinflammation. The proteins involved in waste clearance in the brain and peripheral circulation may be potential biomarkers and drug targets in the early stages of cognitive impairment. This short review focuses on waste clearance dysfunction in AD pathobiology and discusses the improvement of waste clearance as an early intervention in prodromal AD and preclinical stages of dementia.
阿尔茨海默病（AD）是一种具有异质性病因的多因素疾病。阿尔茨海默病的病理学特征是淀粉样β和过度磷酸化的 tau，这是疾病进展的必要条件。许多针对 AD 疾病修饰药物的临床试验未能表明其临床益处。最近基础研究的进展表明，神经炎症在 AD 中起着重要的病理作用。大脑中的损伤相关和病原体相关分子模式诱导神经炎症和炎性小体激活，导致半胱天冬酶-1 依赖性神经胶质和神经元细胞死亡。大脑中的这些废物通过血管周围间隙、血脑屏障和血脑脊液屏障被糖质体系统清除。与年龄相关的血管功能障碍与清除和屏障功能的损害有关，导致神经炎症。大脑和外周循环中参与废物清除的蛋白质可能是认知障碍早期的潜在生物标志物和药物靶点。这篇简短的综述重点介绍了 AD 病理生理学中废物清除功能障碍，并讨论了改善废物清除作为前驱 AD 和痴呆临床前阶段的早期干预措施的潜力。
