Astrocyte‐specific loss of lactoferrin influences neuronal structure and function by interfering with cholesterol synthesis
Astrocyte‐specific loss of lactoferrin influences neuronal structure and function by interfering with cholesterol synthesis
复制标题
DOI：
10.1002/glia.24259
复制
发表时间：
2022-08
期刊：
影响因子：
6.2
通讯作者：
Shuang-feng Xu;Zhong-qiu Pang;Yong-gang Fan;Yan-hui Zhang;Yuhan Meng;Chen-yang Bai;Mengfan Jia;Yan-Hong Chen;Zhan-You Wang;Chuang Guo
中科院分区：
文献类型：
--
作者：
Shuang-feng Xu;Zhong-qiu Pang;Yong-gang Fan;Yan-hui Zhang;Yuhan Meng;Chen-yang Bai;Mengfan Jia;Yan-Hong Chen;Zhan-You Wang;Chuang Guo
越来越多的证据表明，循环乳铁蛋白（Lf）与外周胆固醇代谢紊乱有关。已经出现的是，Lf的分布变化的星形胶质细胞老化的大脑和那些表现出神经退行性疾病，然而，其生理和/或病理作用仍然未知。在这里，我们证明了星形胶质细胞特异性敲除Lf（指定为cKO）导致小鼠早期体重减轻和认知异常。因此，cKO小鼠中神经元生长和突触结构减少。重要的是，原代星形胶质细胞中的Lf缺乏导致固醇调节元件结合蛋白2（Srebp 2）激活和胆固醇产生减少，并且cKO小鼠和/或星形胶质细胞中的胆固醇含量通过外源性Lf或Srebp 2激动剂恢复。此外，神经元树突的复杂性和总树突的长度与cKO小鼠来源的原代星形胶质细胞的培养基培养后减少，这种减少被逆转后胆固醇补充。或者，这些改变与AMP活化蛋白激酶（AMPK）的激活和SREBP 2核转位的抑制有关。这些数据表明，星形胶质细胞Lf可能直接或间接地控制原位胆固醇合成，这可能涉及神经发育和一些神经系统疾病。
Growing evidence indicates that circulating lactoferrin (Lf) is implicated in peripheral cholesterol metabolism disorders. It has emerged that the distribution of Lf changes in astrocytes of aging brains and those exhibiting neurodegeneration; however, its physiological and/or pathological role remains unknown. Here, we demonstrate that astrocyte‐specific knockout of Lf (designated cKO) led to decreased body weight and cognitive abnormalities during early life in mice. Accordingly, there was a reduction in neuronal outgrowth and synaptic structure in cKO mice. Importantly, Lf deficiency in the primary astrocytes led to decreased sterol regulatory element binding protein 2 (Srebp2) activation and cholesterol production, and cholesterol content in cKO mice and/or in astrocytes was restored by exogenous Lf or a Srebp2 agonist. Moreover, neuronal dendritic complexity and total dendritic length were decreased after culture with the culture medium of the primary astrocytes derived from cKO mice and that this decrease was reversed after cholesterol supplementation. Alternatively, these alterations were associated with an activation of AMP‐activated protein kinase (AMPK) and inhibition of SREBP2 nuclear translocation. These data suggest that astrocytic Lf might directly or indirectly control in situ cholesterol synthesis, which may be implicated in neurodevelopment and several neurological diseases.