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Dissect regulation of glial nets surrounding amyloid plaques in Alzheimer's disease

剖析阿尔茨海默病中淀粉样斑块周围神经胶质网的调节

基本信息

批准号：
10467139
负责人：
Roland Horst Friedel
金额：
$ 180万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-05 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10467139
关键词：
APP-PS1 Abeta clearance Ablation Address Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid Amyloid deposition Anatomy Apolipoprotein E Astrocytes Attenuated Behavioral Bioinformatics Biological Assay Biology Cell Nucleus Cells Clinical Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Communication Computer Analysis Data Dependence Deposition Disease Progression Electrophysiology (science)Functional disorder Gene Expression Genes Genetic Transcription Genetic study Human Immunohistochemistry Inflammatory Investigation Late Onset Alzheimer Disease Link Mediating Microglia Modeling Molecular Mus Mutant Strains Mice Nerve Degeneration Neurons Outcome Pathogenesis Pathology Pathway Analysis Physiological Processes Pilot Projects Play Process Regulation Role Secure Senile Plaques Series Signal Transduction Structure Surveys System Tauopathies Testing Up-Regulation aged axon guidance base cell type cognitive function cognitive performance cohort data modeling gene network genomic data glial activation improved in vivo induced pluripotent stem cell inflammatory milieu insight interdisciplinary approach mouse genetics mouse model multidisciplinary mutant neuroinflammation neurotoxicity neurotransmission novel novel therapeutics plexin receptor response risk variant single-cell RNA sequencing tau Proteins transcriptome sequencing transcriptomics β-amyloid burden

项目摘要

PROJECT SUMMARY The pathophysiology of Alzheimer’s disease (AD) remains unclear. Amyloid plaques are surrounded by reactive astrocytes and microglia, forming glial nets that affect amyloid spreading and inflammatory milieu. However, the mechanisms of inter-glial communication in glial nets are poorly understood. Our recent integrated network analysis of -omics data from late-onset AD patients identified the axon guidance receptor Plexin-B1 as a hub gene in an astrocyte-specific subnetwork. We have confirmed that Plexin-B1 is predominantly expressed in astrocytes and that it is upregulated in glial nets of AD patients. Remarkably, our pilot study with an amyloidogenic mouse model of AD showed that Plexin-B1 deletion markedly altered the structure of peri-plaque glial nets. Plexin-B1 deletion resulted in attenuated astrocyte reactivity, reduced cellular spacing of glial nets, and a higher coverage of plaques by microglia, leading to a shift of plaques to a dense core type. These changes of glial nets were associated with an overall reduction in plaque burden and neuritic dystrophy. Here we will expand our preliminary studies to further test the central hypothesis that glial activation and cellular interactions in glial nets, as regulated by Plexin-B1, affect amyloid aggregates and neurotoxicity in AD. Blocking Plexin-B1 may thus present a new opportunity to attenuate astrocyte reactivity in glial nets, reducing amyloid burden and neuroinflammation, thereby slowing down AD progression. In Aim 1, we aim to build cell type-specific glial signaling networks in AD, and to identify Plexin-B1-mediated gene modules in glial nets. We will analyze single cell transcriptomic data from both AD patients and AD mice (with and without Plexin-B1 deletion) to define coregulated gene networks in reactive astrocytes and activated microglia that are associated with Plexin-B1 signaling. In Aim 2, we will carry out a series of functional assays in glial cultures to study the role of Plexin-B1 in mediating astrocyte activation upon amyloid challenge. Human iPSC-derived astrocytes with Plexin-B1 deletion by CRISPR-Cas will be compared to primary astrocytes from Plexin-B1 mutant mice. We will then model in astrocyte/microglia co-cultures glial interactions in response to amyloid challenge in dependence of Plexin- B1. In Aim 3, we will conduct in vivo studies using mouse AD models to investigate in detail the impact of Plexin- B1 deletion on glial nets, plaque deposition, neuronal function and cognitive performance. Both an amyloidogenic and a tauopathy model of AD will be evaluated at early and advanced stages. We expect to demonstrate that Plexin-B1 deletion leads to attenuated astrocyte reactivity in glial nets, reduced cellular spacing, increased microglial coverage of amyloid plaques, and a shift to dense-core plaques and thus less neurotoxicity, as indicated by pilot data. Altogether, our study will provide new insights into the contribution of glial nets and Plexin- B1 to the neurodegenerative processes in AD, thus providing new therapeutic angles.

项目总结