Abstract:
CD2-Associated protein (CD2AP) is a candidate susceptibility gene for Alzheimer\'s disease, but its role in the mammalian central nervous system remains largely unknown. We show that CD2AP protein is broadly expressed in the adult mouse brain, including within cortical and hippocampal neurons, where it is detected at pre-synaptic terminals. Deletion of Cd2ap altered dendritic branching and spine density, and impaired ubiquitin-proteasome system activity. Moreover, in mice harboring either one or two copies of a germline Cd2ap null allele, we noted increased paired-pulse facilitation at hippocampal Schaffer-collateral synapses, consistent with a haploinsufficient requirement for pre-synaptic release. Whereas conditional Cd2ap knockout in the brain revealed no gross behavioral deficits in either 3.5- or 12-month-old mice, Cd2ap heterozygous mice demonstrated subtle impairments in discrimination learning using a touchscreen task. Based on unbiased proteomics, partial or complete loss of Cd2ap triggered perturbation of proteins with roles in protein folding, lipid metabolism, proteostasis, and synaptic function. Overall, our results reveal conserved, dose-sensitive requirements for CD2AP in the maintenance of neuronal structure and function, including synaptic homeostasis and plasticity, and inform our understanding of possible cell-type specific mechanisms in Alzheimer\'s Disease.
摘要:
CD2相关蛋白(CD2AP)是阿尔茨海默病的候选易感基因,但它在哺乳动物中枢神经系统中的作用还不清楚。我们发现CD2AP蛋白在成年小鼠脑中广泛表达,包括皮质和海马神经元,在突触前的末端检测到。Cd2ap的缺失改变了树突状分支和脊柱密度,泛素-蛋白酶体系统活性受损。此外,在携带一个或两个种系Cd2ap无效等位基因拷贝的小鼠中,我们注意到海马Schaffer侧支突触的成对脉冲促进增加,与突触前释放的单倍体不足要求一致。而大脑中的条件性Cd2ap敲除显示在3.5或12个月大的小鼠中没有明显的行为缺陷,Cd2ap杂合小鼠在使用触摸屏任务的辨别学习中表现出细微的损伤。基于无偏见的蛋白质组学,Cd2ap的部分或完全丢失触发了蛋白质的扰动,在蛋白质折叠中起作用,脂质代谢,proteostasis,和突触功能。总的来说,我们的结果揭示了保守的,CD2AP在维持神经元结构和功能方面的剂量敏感性要求,包括突触稳态和可塑性,并告知我们对阿尔茨海默病可能的细胞类型特异性机制的理解。