Systems modeling of shared and distinct molecular mechanisms underlying comorbid Major Depressive Disorder and Alzheimer's disease

阿尔茨海默病（AD）和重度抑郁症（MDD）的共病是常见的，但无法解释， 常见的遗传变异加速药物合作伙伴-阿尔茨海默病（AMP-AD） 一个程序已经详尽地分析了AD和对照受试者多个脑区的基因表达 通过多个队列，然后进行系统生物学分析，以确定分子网络， 与晚发性AD有关的驾驶员VGF（non-acronymic）是一个排名靠前的AD驱动程序， 多个队列我们发现，海马VGF过表达降低了神经病理学和认知功能， 淀粉样变性的5xFAD小鼠模型中的损伤（Beckmann等，正在审查中），VGF已经 已知与抑郁症有关。其AD网络包括双特异性磷酸酶DUSP4和DUSP4。 DUSP6（分别为MAP激酶磷酸酶2和3），在AD中水平均降低，通过其 淀粉样蛋白前体蛋白/Abeta和Tau的网络，并且我们的小组先前也鉴定为淀粉样蛋白前体蛋白/Abeta和Tau的一部分。 仅在女性中导致MDD的网络。我们发表的和初步的研究进一步证明， 在MDD、海马和PFC中VGF水平降低，并且在这些区域中VGF过表达 在小鼠中具有抗抑郁功效。初步的网络分析进一步识别出（1）免疫模块， 集落刺激因子1受体（CSF1R），一种成年小胶质细胞存活所需的蛋白质，作为一种驱动剂， 在AD加MDD中调节，但在单独AD中上调，和（2）水通道蛋白-4（AQP4），一种脑水通道， 其在AD + MDD中相对于AD下调，在星形胶质细胞终足中表达，并且与AD有关。 我们假设，我们确定的VGF，CSF1R和AQP4因果网络的成员有助于 在小鼠模型和AD患者中的认知下降、抑郁样行为和神经病理学， MDD。在目标1中，高通量转录组学，蛋白质组学和多尺度网络分子建模将 在来自一个新的AD患者队列的背外侧前额叶皮层（DLPFC）上进行， 共病MDD、不伴AD的MDD患者和对照受试者，以确定其他共享和不同的 调节这两种疾病的分子机制。在目标2中，我们建议确定 VGF/DUSP共享网络在MDD和AD共病中发挥作用，通过以下方式确定潜在途径： 其中VGF、DUSP4和DUSP6阻断或延迟认知功能障碍、抑郁样行为， 利用AAV介导的过表达发展神经病理学，包括小胶质细胞变化 APP/PS1小鼠中的策略。在Aim 3中，我们将验证Aim中确定的新型子网络和关键驱动因素 1区分AD合并MDD与单独AD。最初，我们将研究CSF1R/免疫/小胶质细胞， AQP4/星形胶质细胞网络在抑郁样行为、神经病理及基因调控中的作用 表达（转录组学），在APP/PS1小鼠过度表达CSF1R或AQP4，以及CSF1R， 缺乏TYROBP的APP/PS1小鼠，导致正常的免疫模块和补救的认知障碍。

Comorbidity of Alzheimer's disease (AD) and Major Depressive Disorder (MDD) is frequent but unexplained by common genetic variants. Members of the Accelerating Medicines Partnership-Alzheimer's Disease (AMP-AD) program have exhaustively profiled gene expression in multiple brain regions from AD and control subjects through multiple cohorts and then performed systems biology analyses to identify molecular networks and drivers implicated in late onset AD. VGF (non-acronymic) is one of the top ranked AD drivers conserved in multiple cohorts. We show that VGF overexpression in hippocampus reduces neuropathology and cognitive impairment in the 5xFAD mouse model of amyloidosis (Beckmann et al., under review), and VGF is already known to have a role in depression. Its AD network includes the dual-specificity phosphatases DUSP4 and DUSP6 (MAP Kinase Phosphatases 2 and 3, respectively), all reduced in level in AD, connected via their network to Amyloid Precursor Protein/Abeta and Tau, and also previously identified by our group to be part of a network that contributes to MDD in females only. Our published and preliminary studies further demonstrate that VGF levels are reduced in MDD, in hippocampus and PFC, and that VGF overexpression in these regions has antidepressant efficacy in mice. Preliminary network analysis further identifies (1) an immune module with colony stimulating factor 1 receptor (CSF1R), a protein required for adult microglial survival, as a driver down- regulated in AD plus MDD, but up-regulated in AD alone, and (2) aquaporin-4 (AQP4), a brain water channel, which is down-regulated in AD plus MDD vs AD, is expressed in astroglial endfeet, and is implicated in AD. We hypothesize that members of our identified VGF, CSF1R, and AQP4 causal networks contribute to cognitive decline, depression-like behavior, and neuropathology in mouse models and patients with AD and MDD. In Aim 1, high throughput transcriptomics, proteomics, and multiscale network molecular modeling will be carried out on dorsolateral prefrontal cortex (DLPFC) from a new cohort of AD patients with and without comorbid MDD, MDD patients without AD, and control subjects, to identify additional shared and distinct molecular mechanisms that regulate these two diseases. In Aim 2, we propose to determine the role(s) that the VGF/DUSP shared network plays in comorbid MDD plus AD, by determining the underlying pathways by which VGF, DUSP4, and DUSP6 block or delay cognitive dysfunction, depression-like behavior, and the development of neuropathology, including microglial changes, utilizing AAV-mediated overexpression strategies in APP/PS1 mice. In Aim 3, we will validate the novel subnetworks and key drivers identified in Aim 1 that differentiate AD plus MDD from AD alone. Initially, we will investigate CSF1R/immune/microglial and AQP4/astroglial network function in depression-like behavior, neuropathology, and the regulation of gene expression (transcriptomics), in APP/PS1 mice overexpressing either CSF1R or AQP4, and also for CSF1R, in APP/PS1 mice that lack TYROBP, resulting in a normalized immune module and rescued cognitive impairment.