Optimal functioning of neuronal networks is critical to the complex cognitive processes of memory and executive function that deteriorate in Alzheimer's disease (AD). Here we use cellular and animal models as well as human biospecimens to show that AD-related stressors mediate global disturbances in dynamic intra- and inter-neuronal networks through pathologic rewiring of the chaperome system into epichaperomes. These structures provide the backbone upon which proteome-wide connectivity, and in turn, protein networks become disturbed and ultimately dysfunctional. We introduce the term protein connectivity-based dysfunction (PCBD) to define this mechanism. Among most sensitive to PCBD are pathways with key roles in synaptic plasticity. We show at cellular and target organ levels that network connectivity and functional imbalances revert to normal levels upon epichaperome inhibition. In conclusion, we provide proof-of-principle to propose AD is a PCBDopathy, a disease of proteome-wide connectivity defects mediated by maladaptive epichaperomes.

中文翻译：

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Epichaperome 是有毒海马应激的介质，会导致基于蛋白质连接的功能障碍。

神经元网络的最佳功能对于阿尔茨海默病 (AD) 中恶化的记忆和执行功能的复杂认知过程至关重要。在这里，我们使用细胞和动物模型以及人类生物样本来表明 AD 相关的压力源通过将伴侣系统病理性重新连接到外层结构来介导动态神经元内部和神经元间网络中的全局干扰。这些结构提供了蛋白质组范围连接的骨架，反过来，蛋白质网络受到干扰并最终功能失调。我们引入术语基于蛋白质连接的功能障碍 (PCBD) 来定义这种机制。对 PCBD 最敏感的是在突触可塑性中起关键作用的通路。我们在细胞和靶器官水平表明，网络连接和功能失衡在外附体抑制后恢复到正常水平。总之，我们提供了原理证明，以提出 AD 是一种 PCBD 病，一种由适应不良的表体细胞介导的蛋白质组范围连接缺陷的疾病。