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

对共病重度抑郁症和阿尔茨海默病潜在的共享和不同分子机制进行系统建模

• 批准号: 10172822
• 负责人: MICHELLE E EHRLICH
• 金额: $ 98.42万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10172822
• 关键词: APP-PS1; Actins; Adult; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloidosis; Antidepressive Agents; Bayesian Analysis; Behavior; Bioinformatics; Biological Markers; Biological Models; Brain; Brain region; Brain-Derived Neurotrophic Factor; Cognitive deficits; DNA; DUSP1 gene; DUSP3 gene; DUSP6 protein; Data; Data Set; Dementia; Development; Disease; Family; Female; Gene Expression; Gene Expression Regulation; Gene Proteins; Genes; Genetic; Genomics; Hippocampus (Brain); Hyperactivity; Immune; Immunologic Receptors; Impaired cognition; Intervention; Knockout Mice; Late Onset Alzheimer Disease; MAPK phosphatase; Macrophage Colony-Stimulating Factor Receptor; Major Depressive Disorder; Manic; Mediating; Medicine; Mental Depression; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mus; Names; Nature; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Peptides; Phosphoric Monoester Hydrolases; Play; Prefrontal Cortex; Proteins; Proteomics; Public Health; Publishing; RNA; Refractory; Role; Specificity; Systems Biology; TYROBP gene; Testing; Tissue Sample; Transgenic Organisms; Validation; Variant; abeta oligomer; aquaporin 4; astrogliosis; behavioral phenotyping; cohort; comorbid depression; comorbidity; depression model; differential expression; disorder control; exhaustion; frontal lobe; genetic variant; member; mild cognitive impairment; molecular modeling; mouse model; multiple omics; network models; neuroinflammation; neuropathology; neuropsychiatric disorder; novel; overexpression; programs; prospective; protein expression; sexual dimorphism; tau Proteins; transcriptomics; validation studies; water channel

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.

阿尔茨海默病 (AD) 和重度抑郁症 (MDD) 合并症很常见，但无法解释 常见的遗传变异。加速药物合作伙伴关系 - 阿尔茨海默病 (AMP-AD) 成员 程序详尽地分析了 AD 和对照受试者多个大脑区域的基因表达 通过多个队列，然后进行系统生物学分析来识别分子网络和 与迟发性 AD 相关的驾驶员。 VGF（非首字母缩略词）是最受保护的 AD 驱动程序之一 多个队列。我们发现海马中的 VGF 过度表达可降低神经病理学和认知能力 5xFAD 小鼠淀粉样变模型中的损伤（Beckmann 等人，正在审查中），并且 VGF 已经 已知对抑郁症有一定作用。其 AD 网络包括双特异性磷酸酶 DUSP4 和 DUSP6（分别为 MAP 激酶磷酸酶 2 和 3），在 AD 中水平均降低，通过其连接 淀粉样前体蛋白/Abeta 和 Tau 的网络，并且之前也被我们的小组识别为 仅导致女性 MDD 的网络。我们已发表的初步研究进一步证明 MDD、海马和 PFC 中的 VGF 水平降低，并且这些区域中 VGF 过度表达 对小鼠有抗抑郁作用。初步网络分析进一步确定了 (1) 一个免疫模块 集落刺激因子 1 受体 (CSF1R) 是成年小胶质细胞生存所需的蛋白质，作为驱动因素 在 AD 加 MDD 中受到调节，但在单独 AD 中上调，以及 (2) 水通道蛋白 4 (AQP4)，一种脑水通道， 与 AD 相比，它在 AD 加 MDD 中下调，在星形胶质细胞末足中表达，并与 AD 相关。 我们假设我们确定的 VGF、CSF1R 和 AQP4 因果网络的成员有助于 小鼠模型和 AD 患者的认知能力下降、抑郁样行为和神经病理学 医学博士。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 对一组新的 AD 患者的背外侧前额叶皮层 (DLPFC) 进行 共病 MDD、无 AD 的 MDD 患者和对照受试者，以确定其他共同的和不同的 调节这两种疾病的分子机制。在目标 2 中，我们建议确定以下角色： VGF/DUSP 共享网络通过确定潜在途径，在共病 MDD 和 AD 中发挥作用 其中 VGF、DUSP4 和 DUSP6 可以阻断或延迟认知功能障碍、抑郁样行为以及 利用 AAV 介导的过度表达进行神经病理学的发展，包括小胶质细胞的变化 APP/PS1 小鼠的策略。在目标 3 中，我们将验证目标中确定的新型子网络和关键驱动因素 1 区分 AD 加 MDD 和单独 AD。首先，我们将研究 CSF1R/免疫/小胶质细胞和 AQP4/星形胶质细胞网络在抑郁样行为、神经病理学和基因调控中的作用 表达（转录组学），在过度表达 CSF1R 或 AQP4 的 APP/PS1 小鼠中，以及 CSF1R，在 缺乏 TYROBP 的 APP/PS1 小鼠导致免疫模块正常化并挽救了认知障碍。