The choroid plexus transcriptome reveals changes in type I and II interferon responses in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disease characterized by a marked decline in cognition and memory formation. Increasing evidence highlights the essential role of neuroinflammatory and immune-related molecules, namely the ones that are produced at the brain barriers, on brain immune surveillance, cellular dysfunction and amyloid beta (Abeta) pathology in AD. Therefore, understanding the response at the brain barriers may unravel novel pathways that are relevant for the pathophysiology of AD. Herein, we focused on the study of the choroid plexus (CP), which constitutes the blood-cerebrospinal fluid barrier, in aging and in AD. Specifically, we used the PDGFB-APPSwInd (J20) transgenic mouse model of AD, which presents early memory decline and progressive Abeta accumulation, and littermate age-matched wild-type (WT) mice, to characterize the CP transcriptome at 3, 5-6 and 11-12 months of age. The most striking observation was that the CP of J20 mice displayed an overall overexpression of type I interferon (IFN) response genes at all ages. Moreover, J20 mice presented a high expression of type II IFN genes in the CP at 3 months, which became lower than WT at 5-6 and 11-12 months. Importantly, along with a marked memory impairment and increased glial activation, J20 mice also presented a similar overexpression of type I IFN genes in the dorsal hippocampus at 3 months. Altogether, these findings provide new insights on a possible interplay between type I and type II IFN responses in AD and point to IFNs as mediators of cognitive decline in aging and in AD. The CP transcriptome of at least 3 mice of each age (3, 5-6 and 11-12 months) and of each genotype (WT or J20) was analyzed and compared.阿尔茨海默病（Alzheimer's disease, AD）是一种以认知与记忆形成能力显著衰退为特征的神经退行性疾病。越来越多的研究证据表明，脑屏障部位产生的神经炎症与免疫相关分子，在AD的脑免疫监视、细胞功能异常以及β淀粉样蛋白（amyloid beta, Aβ）病理进程中发挥着关键作用。因此，解析脑屏障处的分子应答机制，有望揭示与AD病理生理学相关的全新通路。本研究聚焦于衰老及AD状态下构成血-脑脊液屏障的脉络丛（choroid plexus, CP）。具体而言，我们采用了表现出早期记忆衰退与进行性Aβ积累的PDGFB-APPSwInd（J20）转基因AD小鼠模型，以及同窝出生的年龄匹配野生型（wild-type, WT）小鼠，对3、5~6和11~12月龄小鼠的CP转录组进行了表征分析。最引人注目的发现是，在所有检测月龄中，J20小鼠的CP均呈现出I型干扰素（interferon, IFN）应答基因的整体过表达。此外，J20小鼠在3月龄时的CP中II型干扰素基因表达水平较高，但在5~6和11~12月龄时其表达量低于WT小鼠。值得注意的是，除了出现显著的记忆损伤与胶质细胞激活外，J20小鼠在3月龄时的背侧海马体中也呈现出类似的I型干扰素基因过表达现象。综上，本研究结果为AD中I型与II型干扰素应答之间可能存在的相互作用提供了新的见解，并指出干扰素是衰老与AD过程中认知衰退的介导因子。本研究对每个月龄（3、5~6和11~12月龄）、每种基因型（WT或J20）至少3只小鼠的CP转录组进行了分析与比较。