Department of Neurosciences, Case Western Reserve University, Cleveland, OH, USA.
Beijing Tiantan Hospital, Capital Medical University, No.119, S 4th Ring W Rd, Fengtai District, Beijing, 100070, China.
J Neuroinflammation. 2022 Mar 2;19(1):61. doi: 10.1186/s12974-022-02422-0.
Vacuolar sorting protein 35 (VPS35), a key component of the retromer, plays an essential role in selectively retrieval of transmembrane proteins from endosomes to trans-Golgi networks. Dysfunctional retromer is a risk factor for neurodegenerative disorders, including Alzheimer's disease (AD). Microglial VPS35 deficiency is found in AD patients' brain; however, it remains unclear if and how microglial VPS35-loss contributes to AD development.
We used mice with VPS35 cKO (conditional knockout) in microglial cells in 5XFAD, an AD mouse model. The AD related brain pathology (Aβ and glial activation), behavior, and phagocytosis of Aβ were accessed by a combination of immunofluorescence staining analyses and neurological behavior tests.
A decrease in learning and memory function, but increases in insoluble, fibrillar, and plaques of β-amyloids (Aβ), dystrophic neurites, and reactive astrocytes are observed in microglial VPS35 deficient 5XFAD mice. Further examining microglial phenotype demonstrates necessity of microglial VPS35 in disease-associated microglia (DAM) development and microglial uptake of Aβ, revealing a tight association of microglial Aβ uptake with DAM development.
Together, these results uncovered a mechanism by which microglial VPS35-deficiency precipitates AD pathology in 5XFAD mice likely by impairing DAM development and DAM mediated Aβ uptake and clearance, and thus accelerating the cognition decline.
液泡分选蛋白 35（VPS35）是参与选择性回收跨膜蛋白从内体到反式高尔基体网络的再循环体的关键组成部分。功能失调的再循环体是神经退行性疾病的风险因素，包括阿尔茨海默病（AD）。在 AD 患者的大脑中发现了小胶质细胞 VPS35 缺陷；然而，尚不清楚小胶质细胞 VPS35 缺失是否以及如何导致 AD 的发展。
我们使用小胶质细胞 VPS35 cKO（条件性敲除）的 5XFAD 小鼠模型，来研究 AD 相关的脑病理（Aβ 和神经胶质激活）、行为和 Aβ 的吞噬作用。通过免疫荧光染色分析和神经行为测试相结合，来评估 AD 相关脑病理。
在小胶质细胞 VPS35 缺失的 5XFAD 小鼠中，观察到学习和记忆功能下降，但可溶性、纤维状和斑块状β-淀粉样蛋白（Aβ）、神经突营养不良和反应性星形胶质细胞增加。进一步研究小胶质细胞表型表明，小胶质细胞 VPS35 在疾病相关小胶质细胞（DAM）的发育和小胶质细胞摄取 Aβ中是必需的，揭示了小胶质细胞摄取 Aβ与 DAM 发育之间的紧密关联。
这些结果揭示了小胶质细胞 VPS35 缺失导致 5XFAD 小鼠 AD 病理的机制，可能是通过损害 DAM 发育和 DAM 介导的 Aβ摄取和清除，从而加速认知下降。
