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.

晚发性阿尔茨海默病（LOAD）是痴呆的最常见形式，并且其特征在于初始的阿尔茨海默病（AD）。 记忆力减退，认知功能逐渐衰退加速药物的成员 合作伙伴-阿尔茨海默病（AMP-AD）计划已经详尽地分析了多个基因表达， 大脑区域从多个队列的AD和对照组，然后进行系统生物学 分析以识别与LOAD有关的分子网络和驱动程序。VGF（non-acronymic）是一种 几个组确定的排名靠前的AD驱动程序。此外，生物标志物研究一直在确定 在患有神经变性疾病（包括AD）的患者的脑和CSF中降低的VGF水平，并且显示 VGF也是AD进展的强有力的候选生物标志物，CSF中VGF水平降低10 在患病患者中，而不是对照组。我们已经发现海马中VGF的过度表达 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， 在5xFAD小鼠淀粉样变性模型中， (icv)输注VEGF衍生的神经肽TLQP-21或TLQP-62（由其N-末端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， 印刷中）。TLQP-21激活补体C3 aR 1 G蛋白偶联受体（GPCR），一种AD调节剂 在CNS中表达于神经元、小胶质细胞和星形胶质细胞上的致病性。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 利用一种新的LOAD小鼠模型，该模型由晚期- AD发作（MODEL-AD）联盟。这种人源化Abeta敲入系（hAbeta-KI）表达小鼠β 一种含有3个氨基酸取代的淀粉样蛋白，这些氨基酸取代存在于人淀粉样蛋白中（G5 R、F10 Y、R13 H）， A β 40和A β 42，并导致不溶性A β聚集体的形成。不同于转基因5xFAD 家族性早发性AD模型，其表达具有5个家族性突变的人APP和早老素，以及 发生快速、强烈的淀粉样蛋白病，纯合hAbetaKI小鼠不过度表达APP， 出现神经病理学，在18个月大时可检测到，包括不溶性Abeta 40显著增加 和42，可溶性A β减少，海马淀粉样蛋白负荷增加，LTP受损。一个具体目标是 在本补充中提出的，这将严格扩展父项目的调查负载模型。 本研究的目的是：（1）研究VGF调节肿瘤进展的潜在途径， 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/C3 aR 1信令。将采用综合方法来确定如何 改变的VGF或TLQP-21水平影响hAbeta-KI中的小胶质细胞和神经元疾病相关网络 小鼠，提供了关键的新见解的适用性和疗效的VGF治疗迟发性AD。