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）是最常见的痴呆症形式，其特点是初始