Zhao Danrui, Wang Junting, Zhu Yirui, Zhang Hao, Ni Chenkang, Zhao Zhuowen, Dai Jingyu, He Rongqiao, Liu Guangzhi, Gan Cheng, Zhang Shouzi, Tong Zhiqian
Beijing Geriatric Hospital, Beijing, 100095, People's Republic of China.
Westlake Univ, Sch Life Sci, Hangzhou, Zhejiang, People's Republic of China.
Transl Neurodegener. 2025 Sep 24;14(1):49. doi: 10.1186/s40035-025-00510-8.
The glymphatic system serves as the brain's clearance system. It deteriorates with age and is a significant contributor to the onset and progression of Alzheimer's disease (AD). Modulating cerebrospinal fluid (CSF)-based clearance and targeting key components of the glymphatic system, such as aquaporin-4, can enhance amyloid-beta (Aβ) clearance. Light therapy is emerging as a potential AD treatment approach, which involves the use of visible and near-infrared light at specific wavelengths (630/680/808/850/1070 nm), photosensitive proteins, and sensory stimulation at particular frequencies (e.g., 40 Hz). This phototherapy strategy can broadly influence the intracerebral fluid dynamics, including cerebral blood flow, CSF, and interstitial fluid (ISF), as well as structures related to the glymphatic system, such as vascular endothelial cells, glial cells, and neurons. Additionally, it may directly or indirectly inhibit Aβ accumulation by modulating endogenous small molecules, thereby improving cognitive function. Our previous research demonstrated that 630-nm red light can inhibit Aβ cross-linking by clearing endogenous formaldehyde and promoting ISF drainage. Notably, Aβ accumulation exhibits distinct characteristics at different phases of AD, accompanied by varying features of glymphatic system impairment. In the early stages, deep brain regions are significantly affected, whereas in the late stages, accumulation primarily occurs in the paracentral, precentral, and postcentral cortices. Owing to the limited penetration depth of light, this may pose a challenge to the clinical efficacy of phototherapy. Therefore, different stages of AD may require tailored phototherapeutic strategies. Meanwhile, it is important to acknowledge the ongoing controversies associated with lymphovenous anastomosis, a procedure that targets the glymphatic system. Therefore, this article reviews the characteristics of glymphatic system impairment across various AD stages and the mechanisms by which effective phototherapies modulate the glymphatic system. Potential phototherapeutic strategies corresponding to different stages of Aβ accumulation are also proposed.
类淋巴系统是大脑的清除系统。它会随着年龄增长而退化，并且是阿尔茨海默病（AD）发病和进展的重要因素。调节基于脑脊液（CSF）的清除并靶向类淋巴系统的关键成分，如水通道蛋白4，可以增强β淀粉样蛋白（Aβ）的清除。光疗法正在成为一种潜在的AD治疗方法，它涉及使用特定波长（630/680/808/850/1070纳米）的可见光和近红外光、光敏蛋白以及特定频率（如40赫兹）的感觉刺激。这种光疗策略可以广泛影响脑内流体动力学，包括脑血流量、脑脊液和间质液（ISF），以及与类淋巴系统相关的结构，如血管内皮细胞、神经胶质细胞和神经元。此外，它可能通过调节内源性小分子直接或间接抑制Aβ积累，从而改善认知功能。我们之前的研究表明，630纳米的红光可以通过清除内源性甲醛和促进ISF引流来抑制Aβ交联。值得注意的是，Aβ积累在AD的不同阶段表现出不同的特征，同时伴有类淋巴系统损伤的不同特征。在早期，深部脑区受到显著影响，而在晚期，积累主要发生在中央旁、中央前和中央后皮质。由于光的穿透深度有限，这可能对光疗的临床疗效构成挑战。因此，AD的不同阶段可能需要量身定制的光疗策略。同时，必须认识到与针对类淋巴系统的淋巴管静脉吻合术相关的持续争议。因此，本文综述了AD各阶段类淋巴系统损伤的特征以及有效光疗法调节类淋巴系统的机制。还提出了与Aβ积累不同阶段相对应的潜在光疗策略。
