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: 10214197
• 负责人: MICHELLE E EHRLICH
• 金额: $ 28.23万
• 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 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10214197
• 关键词: Actins; Administrative Supplement; Age-Months; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer’s disease biomarker; Amino Acid Substitution; Amino Acids; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; Amyloidosis; Animal Model; Animals; Astrocytes; Behavior; Binding; Biological Markers; Biological Models; Brain; Brain region; Brain-Derived Neurotrophic Factor; C-terminal; C3AR1 gene; CHGB gene; Chronic; Cognitive; Complement; Complement Receptor; Data; Dementia; Development; Disease; Disease Progression; Dorsal; Early Onset Familial Alzheimer' s Disease; Evaluation; Frontotemporal Dementia; Funding; G-Protein-Coupled Receptors; Gender; Gene Expression; Genes; Genetic study; Genomic approach; Genomics; Head; Hippocampus (Brain); Human; Human Amyloid Precursor Protein; ITGAM gene; ITGB2 gene; Impaired cognition; Impairment; Infusion procedures; Investigation; Knock-in; Knock-in Mouse; Late Onset Alzheimer Disease; Length; Longitudinal cohort; Major Depressive Disorder; Maps; Medicine; Memory Loss; Mental Depression; Microglia; Modeling; Molecular; Mus; Mutation; N-terminal; Names; Neurodegenerative Disorders; Neurons; Neuropeptides; Pathogenesis; Pathology; Pathway interactions; Patients; Peptides; Phenotype; Prefrontal Cortex; Presenile Alzheimer Dementia; Proteins; RNA; Regulation; Research; Senile Plaques; Signal Transduction; Systems Biology; TYROBP gene; Therapeutic; Time; Transgenic Mice; Transgenic Organisms; Treatment Efficacy; VGF protein; Vesicle; amyloid pathology; astrogliosis; base; candidate marker; cognitive function; cohort; comorbidity; complement 1q receptor; complement system; density; disorder control; exhaustion; frontal lobe; insight; member; mouse model; mutant; neurogenesis; neuropathology; novel; overexpression; parent project; pre-clinical; presenilin; presenilin-1; programs; tau Proteins; tau mutation; webinar

Late onset Alzheimer's disease (LOAD) is the most common form of dementia, and is characterized by initial memory loss and then a progressive decline in cognitive function. Members of the Accelerating Medicines Partnership-Alzheimer's Disease (AMP-AD) program have exhaustively profiled gene expression in multiple brain regions from multiple cohorts of AD and control subjects, and have then performed systems biology analyses to identify molecular networks and drivers implicated in LOAD. VGF (non-acronymic) is one of the top ranked AD drivers identified by several groups. Moreover, biomarker studies have consistently identified reduced VGF levels in the brains and CSF of patients with neurodegenerative disease including AD, and show that VGF is also a strong candidate biomarker of AD progression, with a 10% decrease in CSF levels of VGF per year in diseased patients but not controls. We have shown that VGF overexpression in hippocampus reduces cortical and hippocampal amyloid deposition, microgliosis, astrogliosis, and cognitive impairment, and rescues neurogenesis deficits, in the 5xFAD mouse amyloidosis model, while chronic intracerebroventricular (icv) infusion of the VGF-derived neuropeptides TLQP-21 or TLQP-62 (named by its N-terminal 4 amino acids and length) has similar effects (El Gaamouch et al., Mol Neurodegener 2020; Beckmann et al., Nat Commun, in press). TLQP-21 activates the complement C3aR1 G-protein coupled receptor (GPCR), a regulator of AD pathogenesis that is expressed in the CNS on neurons, microglia, and astrocytes. The mechanism(s) of action of TLQP-21 to modulate AD neuropathology will be further investigated in this administrative supplement utilizing a novel LOAD mouse model developed by the Model Organism Development and Evaluation of Late- Onset AD (MODEL-AD) consortium. This humanized Abeta knockin line (hAbeta-KI) expresses mouse beta amyloid that contains 3 amino acid substitutions, which are found in human amyloid (G5R, F10Y, R13H), in Abeta40 and Abeta42, and result in the formation of insoluble Abeta aggregates. Unlike the transgenic 5xFAD model of familial early onset AD, that expresses human APP and presenilin with 5 familial mutations, and develops a rapid, robust amyloidopathy, homozygous hAbetaKI mice do not overexpress APP, and slowly develop neuropathology, detectable at 18 months of age, including significantly increased insoluble Abeta40 and 42, reduced soluble Abeta, increased hippocampal amyloid load, and impaired LTP. One specific aim is proposed in this supplement, which will critically extend the parent project's investigation to a LOAD model. This aim proposes (1) to study the underlying pathways by which VGF modulates progression of neuropathology in the hAbeta-KI model, (2) to develop cohorts for long-term analysis, and (3) to determine whether VGF actions require TLQP-21/C3aR1 signaling. Integrative approaches will be used to determine how altered VGF or TLQP-21 levels impact microglial and neuronal disease-associated networks in hAbeta-KI mice, providing critical new insights into the applicability and efficacy of VGF therapeutics in late onset AD.

晚发性阿尔茨海默氏病 (LOAD) 是最常见的痴呆症，其特征是初始 记忆丧失，然后认知功能逐渐下降。加速药物成员 合作阿尔茨海默氏病 (AMP-AD) 计划已详尽分析了多种疾病中的基因表达情况 来自多个 AD 群体和对照受试者的大脑区域，然后进行系统生物学 分析以确定与 LOAD 相关的分子网络和驱动因素。 VGF（非缩写）是其中之一 由多个团体确定的排名最高的 AD 驱动程序。此外，生物标志物研究一致发现 神经退行性疾病（包括 AD）患者大脑和脑脊液中的 VGF 水平降低，并显示 VGF 也是 AD 进展的有力候选生物标志物，脑脊液中 VGF 水平下降 10% 每年在患病患者中进行，但在对照组中则不然。我们已经证明海马中 VGF 过度表达 减少皮质和海马淀粉样蛋白沉积、小胶质细胞增生、星形胶质细胞增生和认知障碍，以及 在 5xFAD 小鼠淀粉样变性模型中挽救神经发生缺陷，而慢性脑室内 (icv) 输注 VGF 衍生的神经肽 TLQP-21 或 TLQP-62（以其 N 端 4 个氨基酸命名） 和长度）具有类似的效果（El Gaamouch 等人，Mol Neurodegener 2020；Beckmann 等人，Nat Commun， 正在出版）。 TLQP-21 激活补体 C3aR1 G 蛋白偶联受体 (GPCR)，这是 AD 的调节因子 发病机制在中枢神经系统的神经元、小胶质细胞和星形胶质细胞上表达。作用机制 TLQP-21 调节 AD 神经病理学的作用将在本行政补充中进一步研究 利用模型生物开发和评估最新开发的新型 LOAD 小鼠模型 发作 AD (MODEL-AD) 联盟。这种人源化 Abeta 敲入系 (hAbeta-KI) 表达小鼠 β 淀粉样蛋白含有 3 个氨基酸取代，这些氨基酸取代存在于人类淀粉样蛋白（G5R、F10Y、R13H）中 Abeta40 和 Abeta42，并导致不溶性 Abeta 聚集体的形成。与转基因 5xFAD 不同 家族性早发 AD 模型，表达具有 5 个家族突变的人类 APP 和早老素，以及 发展为快速、强烈的淀粉样变性，纯合 hAbetaKI 小鼠不会过度表达 APP，并且缓慢 发展神经病理学，可在 18 个月大时检测到，包括显着增加的不溶性 Abeta40 42、可溶性 Abeta 减少、海马淀粉样蛋白负荷增加、LTP 受损。一个具体目标是 本补充中提出，这将关键地将父项目的调查扩展到 LOAD 模型。 该目标建议 (1) 研究 VGF 调节疾病进展的潜在途径 hAbeta-KI 模型中的神经病理学，(2) 开发用于长期分析的队列，以及 (3) 确定 VGF 动作是否需要 TLQP-21/C3aR1 信号传导。将采用综合方法来确定如何 VGF 或 TLQP-21 水平的改变影响 hAbeta-KI 中的小胶质细胞和神经元疾病相关网络 小鼠，为 VGF 疗法在迟发性 AD 中的适用性和功效提供了重要的新见解。