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: 10404989
• 负责人: MICHELLE E EHRLICH
• 金额: $ 84.3万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10404989
• 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; Black race; 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.

阿尔茨海默氏病（AD）和主要抑郁症（MDD）的合并症经常出现，但无法解释 常见的遗传变异。加速药物合作伙伴关系的成员 - 阿尔茨海默氏病（AMP-AD） 程序在广告和控制受试者的多个大脑区域中详细介绍了基因表达 通过多个队列，然后进行系统生物学分析，以识别分子网络和 驾驶员与后期广告有关。 VGF（非歧义）是保守的排名最高的广告驱动程序之一 多个队列。我们表明，海马中的VGF过表达降低了神经病理学和认知能力 5XFAD小鼠淀粉样变性模型的损害（Beckmann等人，正在综述），VGF已经是 已知在抑郁症中起作用。它的广告网络包括双特异性磷酸酶DUSP4和 DUSP6（分别MAP激酶磷酸酶2和3），AD的水平降低，通过其连接 与淀粉样蛋白前体蛋白/ABETA和TAU的网络，并以前由我们的小组确定为 仅在女性中为MDD做出贡献的网络。我们发表的初步研究进一步证明 在MDD，海马和PFC中，VGF水平降低了，这些区域中的VGF过表达降低 在小鼠中具有抗抑郁剂的功效。初步网络分析进一步识别（1） 菌落刺激因子1受体（CSF1R）是成年小胶质细胞生存所需的蛋白质，作为驱动器下降 在AD和MDD中受到调节，但仅在AD中被上调，并且（2）Aquaporin-4（AQP4），脑水通道， 在AD Plus MDD与AD中被下调的，在星形胶质端的末端表示，与AD有关。 我们假设我们已确定的VGF，CSF1R和AQP4因果网络的成员有助于 小鼠模型和AD和患者的认知能力下降，类似抑郁的行为和神经病理学 MDD。在AIM 1中，高吞吐转录组学，蛋白质组学和多尺度网络分子建模将 可以在新的AD患者和不具有的AD患者队列的背侧外侧前额叶皮层（DLPFC）上进行 合并的MDD，没有AD的MDD患者和对照对象，以识别其他共享和不同 调节这两种疾病的分子机制。在AIM 2中，我们建议确定角色 VGF/DUSP共享网络在合并的MDD Plus AD中播放，通过确定基础途径 VGF，DUSP4和DUSP6阻滞或延迟认知功能障碍，抑郁症行为以及 使用AAV介导的过表达的神经病理学的发展，包括小胶质变化 APP/PS1小鼠的策略。在AIM 3中，我们将验证AIM中确定的新型子网和关键驱动因素 1将广告加上MDD与仅AD区分开。最初，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症状行为，神经病理学和基因调节中 表达式（转录组学），在过表达CSF1R或AQP4的App/PS1小鼠中，也适用于CSF1R 缺乏暴力的APP/PS1小鼠，导致了标准化的免疫模块并挽救了认知障碍。

项目成果

Intranasal Peptide Therapeutics: A Promising Avenue for Overcoming the Challenges of Traditional CNS Drug Development.

• DOI: 10.3390/cells11223629
• 发表时间: 2022-11-16
• 期刊: CELLS
• 影响因子: 6
• 作者: Bose, Meenakshi;Quipildor, Gabriela Farias;Ehrlich, Michelle E.;Salton, Stephen R.
• 通讯作者: Salton, Stephen R.