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; 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.

晚期阿尔茨海默氏病（负载）是最常见的痴呆形式，其特征是初始 记忆丧失，然后认知功能逐渐下降。加速药物的成员 伙伴关系 - 阿尔茨海默氏病（AMP-AD）计划已详尽地介绍了多个基因表达 来自多个AD和对照对象的大脑区域，然后进行了系统生物学 分析以识别与负载有关的分子网络和驱动因素。 VGF（非歧义）是 排名最高的广告驱动程序由几个小组确定。此外，生物标志物研究一致地确定 神经退行性疾病（包括AD）患者的大脑和CSF的VGF水平降低，并显示 该VGF也是AD进展的强大候选生物标志物，CSF的VGF水平降低了10％ 患病患者的每年，但没有对照。我们已经证明了海马中的VGF过表达 减少皮质和海马淀粉样蛋白沉积，小胶质细胞增多症，星形胶质细胞增多和认知障碍，以及 在5XFAD小鼠淀粉样变性模型中，挽救神经发生缺陷，而慢性脑室脑室 （ICV）输注VGF衍生的神经肽TLQP-21或TLQP-62（由其N末端4氨基酸命名 和长度）具有相似的效果（El Gaamouch等，Mol NeuroDegener 2020； Beckmann等，Nat Commun， 在印刷中）。 TLQP-21激活补体C3AR1 G蛋白偶联受体（GPCR），AD的调节剂 在神经元，小胶质细胞和星形胶质细胞的中枢神经系统中表达的发病机理。动作机制 TLQP-21的调节AD神经病理学将在此行政补充中进一步研究 利用模型生物体发展开发的新型负载小鼠模型和晚期评估 发作广告（AD）联盟。该人源化的Abeta敲蛋白线（HABETA-KI）表示鼠标Beta 淀粉样蛋白包含3种氨基酸取代，在人淀粉样蛋白（G5R，F10Y，R13H）中发现 Abeta40和Abeta42，并导致不溶性Abe​​ta聚集体的形成。与转基因5xfad不同 家族性早期发作AD的模型，该模型以5个家族突变表达人类应用和老年蛋白，并且 开发一种快速，健壮的淀粉样疗法，纯合的Habetaki小鼠不会过表达应用，并慢慢 发展神经病理学，可在18个月大的时候检测到，包括显着增加的不溶性Abe​​ta40 42，可溶性ABETA减少，海马淀粉样蛋白负荷增加和LTP受损。一个具体目的是 在此补品中提出的，该补品将严格将父项目的调查扩展到负载模型。 此目的建议（1）研究VGF调节进展的潜在途径 HABETA-KI模型中的神经病理学，（2）开发长期分析的队列，以及（3）确定 VGF动作是否需要TLQP-21/C3AR1信号传导。集成方法将用于确定如何 VGF或TLQP-21水平改变了HABETA-KI中的小胶质细胞和神经元相关网络 小鼠对VGF治疗剂在晚期AD中的适用性和功效提供了关键的新见解。