The divergent effects of astrocyte ceruloplasmin on learning and memory function in young and old mice.
The divergent effects of astrocyte ceruloplasmin on learning and memory function in young and old mice.
复制标题
DOI：
10.1038/s41419-022-05459-4
复制
发表时间：
2022-11-28
影响因子：
9
通讯作者：
Chang, Yan-Zhong
中科院分区：
文献类型：
--
作者：
Li, Zhong-Da;Li, Haiyan;Kang, Shaomeng;Cui, Yan-Ge;Zheng, Huiwen;Wang, Peina;Han, Kang;Yu, Peng;Chang, Yan-Zhong
铜蓝蛋白（CP）在维持铁稳态中起重要作用。Cp基因敲除（Cp-/-）小鼠随着年龄的增长而发生神经退行性疾病，并显示脑中的铁积累。然而，在3 M Cp-/-小鼠中也观察到铁缺乏。使用系统性Cp基因敲除不足以揭示CP在中枢神经系统中的特异性功能。考虑到最近的发现，星形胶质细胞合成的大部分脑CP，我们产生了星形胶质细胞条件性Cp基因敲除（CpGfapcKO）小鼠，并发现铁含量下降，在年轻（6 M）和老年（18 M）CpGfapcKO小鼠的大脑皮层和海马。进一步的实验显示，6 M CpGfapcKO小鼠表现出受损的学习和记忆功能，而18 M CpGfapcKO小鼠表现出改善的学习和记忆功能。我们的研究表明，星形胶质细胞Cp缺失阻断脑铁通过血脑屏障流入，伴随着脑微血管内皮细胞铁水平的增加，导致脑铁缺乏和神经元，星形胶质细胞，小胶质细胞和少突胶质细胞铁蛋白水平下调。在幼年时，CpGfapcKO小鼠的突触密度、突触相关蛋白水平、5-羟色胺和去甲肾上腺素、海马神经发生和髓鞘形成均减少。这些变化影响了年轻CpGfapcKO小鼠的学习和记忆障碍。在老年CpGfapcKO小鼠中，随着衰老的铁积累被减弱，并伴随着ROS-MAPK-细胞凋亡途径、Tau磷酸化和β-淀粉样蛋白聚集的缓解，从而延缓与年龄相关的记忆衰退。总之，我们的研究结果表明，星形胶质细胞Cp缺失通过不同的调节机制诱导的小鼠脑中铁含量减少，对学习和记忆功能具有不同的影响，这可能是预防和治疗痴呆的策略。
Ceruloplasmin (CP) plays an important role in maintaining iron homeostasis. Cp gene knockout (Cp-/-) mice develop a neurodegenerative disease with aging and show iron accumulation in the brain. However, iron deficiency has also been observed in 3 M Cp-/- mice. The use of systemic Cp gene knockout is insufficient to reveal specific functions for CP in the central nervous system. Considering recent discoveries that astrocytes synthetize the majority of brain CP, we generated astrocyte conditional Cp knockout (CpGfapcKO) mice, and found that iron contents decreased in the cerebral cortex and hippocampus of young (6 M) and old (18 M) CpGfapcKO mice. Further experiments revealed that 6 M CpGfapcKO mice exhibited impaired learning and memory function, while 18 M CpGfapcKO mice exhibited improved learning and memory function. Our study demonstrates that astrocytic Cp deletion blocks brain iron influx through the blood-brain-barrier, with concomitantly increased iron levels in brain microvascular endothelial cells, resulting in brain iron deficiency and down-regulation of ferritin levels in neurons, astrocytes, microglia and oligodendrocytes. At the young age, the synapse density, synapse-related protein levels, 5-hydroxytryptamine and norepinephrine, hippocampal neurogenesis and myelin formation were all decreased in CpGfapcKO mice. These changes affected learning and memory impairment in young CpGfapcKO mice. In old CpGfapcKO mice, iron accumulation with aging was attenuated, and was accompanied by the alleviation of the ROS-MAPK-apoptosis pathway, Tau phosphorylation and β-amyloid aggregation, thus delaying age-related memory decline. Overall, our results demonstrate that astrocytic Cp deletion has divergent effects on learning and memory function via different regulatory mechanisms induced by decreased iron contents in the brain of mice, which may present strategies for the prevention and treatment of dementia.
登录
查看更多内容
影响因子：
15.1
作者：
Ayton S;Lei P;Adlard PA;Volitakis I;Cherny RA;Bush AI;Finkelstein DI
通讯作者：
Finkelstein DI
影响因子：
0.7
作者：
Ashrafi F;Salari M;Nouri F;Shiravi F
通讯作者：
Shiravi F
影响因子：
11.2
作者：
Ayton, Scott;Lei, Peng;Finkelstein, David I.
通讯作者：
Finkelstein, David I.
影响因子：
14.5
作者：
Bustos, Fernando J.;Ampuero, Estibaliz;van Zundert, Brigitte
通讯作者：
van Zundert, Brigitte
影响因子：
64.8
作者：
Da Mesquita S;Louveau A;Vaccari A;Smirnov I;Cornelison RC;Kingsmore KM;Contarino C;Onengut-Gumuscu S;Farber E;Raper D;Viar KE;Powell RD;Baker W;Dabhi N;Bai R;Cao R;Hu S;Rich SS;Munson JM;Lopes MB;Overall CC;Acton ST;Kipnis J
通讯作者：
Kipnis J