类淋巴功能障碍作为连接全身健康状况与阿尔茨海默病的多系统通路：机制、危险因素与治疗机会

文献信息

中文摘要

类淋巴系统是一条与胶质细胞相关的血管周围通路，参与脑脊液（CSF）-组织间液（ISF）交换以及包括β-淀粉样蛋白（Aβ）和tau在内的神经毒性代谢物从中枢神经系统的转运和清除。越来越多的证据表明，类淋巴和血管周围清除的改变与阿尔茨海默病（AD）病理相关，并可能促进神经毒性蛋白的蓄积和神经退行性变。本综述探讨类淋巴系统在AD中的作用，并探讨衰老、睡眠障碍、高血压、缺血性心脏病、高脂饮食、糖尿病和肠道微生物群失调如何损害类淋巴转运。在实验模型中反复出现的机制是血管周围AQP4极性的丧失，而血管、代谢和炎症状况可能汇聚于相关的血管周围和神经血管过程，损害CSF-ISF交换和溶质处理。使用DTI-ALPS、血管周围间隙负荷和自由水测量等标志物的神经影像学研究提供了AD中类淋巴相关和血管周围过程改变的证据，并证明其与淀粉样蛋白沉积、神经退行性变和认知下降相关。此外，类淋巴功能障碍可能与神经炎症和tau病理相互作用，形成自我强化的循环，加速疾病进展。新兴治疗策略，包括持续θ爆发刺激、阻塞性睡眠呼吸暂停的正压气道治疗、AQP4功能的药理学增强和营养干预，已在实验和早期转化研究中显示出影响类淋巴相关过程的潜力，并可能减轻AD相关病理。总体而言，当前研究结果提示类淋巴和血管周围清除通路可能是全身健康状况与AD之间的重要联系。由于相关通路涉及多种全身性疾病，针对类淋巴和血管周围功能障碍的干预可能对脑健康具有更广泛的相关性，但其临床效果仍有待确定。

英文摘要

The glymphatic system is a glia-associated perivascular pathway involved in cerebrospinal fluid (CSF)-interstitial fluid (ISF) exchange and the transport and clearance of neurotoxic metabolites, including amyloid-β (Aβ) and tau, from the central nervous system. Growing evidence suggests that alterations in glymphatic and perivascular clearance are associated with Alzheimer's disease (AD) pathology and may contribute to the accumulation of neurotoxic proteins and neurodegeneration. This review examines the role of the glymphatic system in AD and explores how aging, sleep disturbances, hypertension, ischemic heart disease, high-fat diet, diabetes, and gut microbiome dysbiosis impair glymphatic transport. A recurring mechanism across experimental models is the loss of perivascular AQP4 polarization, while vascular, metabolic, and inflammatory conditions may converge on related perivascular and neurovascular processes that impair CSF-ISF exchange and solute handling. Neuroimaging studies using markers such as DTI-ALPS, perivascular space burden, and free-water measurements provide evidence of alterations in glymphatic-related and perivascular processes in AD and demonstrate associations with amyloid deposition, neurodegeneration, and cognitive decline. Furthermore, glymphatic dysfunction may interact with neuroinflammation and tau pathology, creating a self-reinforcing cycle that accelerates disease progression. Emerging therapeutic strategies, including continuous theta-burst stimulation, positive airway pressure therapy for obstructive sleep apnea, pharmacological enhancement of AQP4 function, and nutritional interventions, have shown potential in experimental and early translational studies to influence glymphatic-related processes and may mitigate AD-related pathology. Collectively, current findings suggest that glymphatic and perivascular clearance pathways may represent an important link between systemic health conditions and AD. Because related pathways are implicated across multiple systemic conditions, interventions targeting glymphatic and perivascular dysfunction may have broader relevance to brain health, but their clinical effects remain to be established.