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.

迟发性阿尔茨海默病(LOAD)是痴呆症最常见的形式，其特点是最初 记忆丧失，然后是认知功能的进行性下降。加速医学协会的成员 伙伴关系-阿尔茨海默病(AMP-AD)计划在多个 从AD和对照受试者的多个队列中提取的大脑区域，然后进行系统生物学 分析以确定与负载有关的分子网络和驱动因素。VGF(非首字母缩写)是 由几个组确定的排名靠前的广告司机。此外，生物标记物研究一致地发现 包括AD在内的神经退行性疾病患者脑和脑脊液中VGF水平降低，并显示 VGF也是AD进展的一个强有力的候选生物标志物，脑脊液中VGF水平下降10% 每年在疾病患者中，而不是在对照组中。我们已经证明VGF在海马区过表达 减少皮质和海马区淀粉样蛋白沉积、小胶质细胞增多症、星形胶质细胞增多症和认知障碍，以及 挽救5xFAD小鼠淀粉样变性模型中的神经再生缺陷，同时慢性脑室内 (Icv)输注VGF衍生神经肽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， 在新闻发布会上)。TLQP-21激活AD调节因子补体C3aR1G蛋白偶联受体 在中枢神经系统神经元、小胶质细胞和星形胶质细胞上表达的致病机制。作用机制(S) TLQP-21对AD神经病理的调节作用将在本行政补充资料中进一步研究 利用模型生物体开发和评价的一种新的负荷小鼠模型-- 发病AD(模型-AD)联合体。这种人源化的Abeta敲击线(hAbeta-ki)表达小鼠的Beta 含有3个氨基酸替代的淀粉样蛋白，在人类淀粉样蛋白(G5R，F10Y，R13H)中发现，在 Abeta40和Abeta42，并导致形成不溶的Abeta聚集体。与转基因5xFAD不同 家族性早发性AD模型，表达人类APP和早老素，有5个家族性突变 发展迅速，强健的淀粉样变性，纯合子hAbetaKI小鼠不过度表达APP，并且缓慢 出现神经病理，在18个月大时可检测到，包括显著增加的不溶性Abeta 40 和42，降低可溶性Abeta，增加海马淀粉样蛋白负荷，并损害LTP。一个明确的目标是 这将关键地将父项目的调查扩展到负载模型。 本研究的目的在于：(1)研究血管生长因子调节血管紧张素转换酶进展的潜在途径。 在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操作是否需要TLQP-21/C3aR1信号。将使用综合方法来确定如何 HAbeta-Ki中VGF或TLQP-21水平改变对小胶质细胞和神经元疾病相关网络的影响 为VGF疗法在晚发性阿尔茨海默病中的适用性和有效性提供了关键的新见解。