Origins, properties, and therapeutic potential of cells that repopulate the microglia-depleted adult brain

重新填充小胶质细胞耗尽的成人大脑的细胞的起源、特性和治疗潜力

• 批准号: 10554378
• 负责人: Kim Green
• 金额: $ 37.35万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10554378
• 关键词: Actins; Adult; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Appearance; Astrocytes; Axon; Back; Behavior; Blood Vessels; Brain; Brain Diseases; Cell Proliferation; Cells; Clinical; Clinical Trials; Cognition; Cytoskeleton; Dendritic Spines; Development; Disease; Disease Progression; Endothelial Cells; Gene Expression; Gene Expression Profile; Glial Cell Proliferation; Health; Homeostasis; Inflammation; Injury; Long-Term Potentiation; Macrophage; Macrophage Colony-Stimulating Factor Receptor; Microglia; Modeling; Morphology; Mus; Myelogenous; Myeloid Cells; Neurons; Nucleosomes; Oligodendroglia; Pathology; Pericytes; Phagocytes; Phenotype; Population; Property; Recovery of Function; Rejuvenation; Reporting; Route; Signal Transduction; Source; Stains; Stream; Synapses; Synaptic plasticity; Therapeutic; Time; Tissues; Withdrawal; Work; aging brain; biomarker identification; brain cell; cell type; comparison control; drug withdrawal; functional outcomes; improved; inhibitor; juvenile animal; mouse model; neurogenesis; neuroinflammation; novel; postnatal development; response; restoration; transcriptome; transcriptome sequencing; white matter

Abstract: We discovered microglia in the adult brain are dependent on signaling through the colony-stimulating factor 1 receptor (CSF1R), and identified several CSF1R inhibitors that crossed into the brain, leading to the elimination of most of the microglia. This remarkable phenomenon has been widely replicated and is now a standard in the field to explore microglial function in health and disease, and clinical trials are being conducted/planned as a result. We also found that we could eliminate microglia for as long as we continued treatment, but upon drug withdrawal, repopulation of the microglial tissue occurred rapidly from proliferating cells throughout the brain that formed a new microglial tissue in ~14 days. We found we could use this to “reset” the inflamed microglial tissue after injury or in aging, and promote functional recovery/cognition. In this continuation, we seek to understand the source and properties of these repopulating cells that become microglia, and study how they modulate neuronal gene expression to rejuvenate the aged brain and fully restore long-term potentiation to that of a young animal. In addition, we describe a second slower source of microglial repopulation, that originates in specific brain niches – the rostral migratory stream (RMS) and associated projecting axonal tracts. This “alternative” repopulation is only unmasked by the complete elimination of microglia. These “alternative” cells arise from unknown cells within these brain niches, and eventually can break out from the white matter tracts and fill the cortex/brain. These cells never attain the numbers, morphologies, or gene expression of microglia, but resemble microglia found in the RMS, which have pro-neurogenesis and increased phagocytotic capabilities than other microglia. We will determine the source of these “alternative” cells, and the consequences of filling the brain with them, including if they have any therapeutic potential, in a mouse model of Alzheimer's disease.

文摘:

项目成果

Commentary: How Do Microglia Regulate Neural Circuit Connectivity and Activity in the Adult Brain?

• DOI: 10.1177/26331055211071124
• 发表时间: 2022
• 期刊: Neuroscience insights
• 影响因子: 3.6
• 作者: Liu YJ;Green KN;Holmes TC;Xu X
• 通讯作者: Xu X

Subventricular zone/white matter microglia reconstitute the empty adult microglial niche in a dynamic wave.

• DOI: 10.7554/elife.66738
• 发表时间: 2021-08-23
• 期刊: eLife
• 影响因子: 7.7
• 作者: Hohsfield LA;Najafi AR;Ghorbanian Y;Soni N;Crapser J;Figueroa Velez DX;Jiang S;Royer SE;Kim SJ;Henningfield CM;Anderson A;Gandhi SP;Mortazavi A;Inlay MA;Green KN
• 通讯作者: Green KN

Effects of long-term and brain-wide colonization of peripheral bone marrow-derived myeloid cells in the CNS.

• DOI: 10.1186/s12974-020-01931-0
• 发表时间: 2020-09-20
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3
• 作者: Hohsfield LA;Najafi AR;Ghorbanian Y;Soni N;Hingco EE;Kim SJ;Jue AD;Swarup V;Inlay MA;Green KN
• 通讯作者: Green KN

Gamma oscillations in the entorhinal-hippocampal circuit underlying memory and dementia.

• DOI: 10.1016/j.neures.2018.02.002
• 发表时间: 2018-04
• 期刊: Neuroscience research
• 影响因子: 2.9
• 作者: Nakazono T;Jun H;Blurton-Jones M;Green KN;Igarashi KM
• 通讯作者: Igarashi KM

Microglia influence immune responses and restrict neurologic disease in response to central nervous system infection by a neurotropic murine coronavirus.

• DOI: 10.3389/fncel.2023.1291255
• 发表时间: 2023
• 期刊: FRONTIERS IN CELLULAR NEUROSCIENCE
• 影响因子: 5.3
• 作者: Syage, Amber;Pachow, Collin;Cheng, Yuting;Mangale, Vrushali;Green, Kim N.;Lane, Thomas E.
• 通讯作者: Lane, Thomas E.