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Human Microglial State Dynamics in Alzheimer's Disease Progression

ABSTRACT: Human Microglial State Dynamics in Alzheimer's Disease Progression

PROVIDER: PRJNA944174 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23891518.fastq.gz	Fastqsanger.gz
	SRR23891519.fastq.gz	Fastqsanger.gz
	SRR23891520.fastq.gz	Fastqsanger.gz
	SRR23891521.fastq.gz	Fastqsanger.gz
	SRR23891522.fastq.gz	Fastqsanger.gz

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Project description:Altered microglial states affect neuroinflammation, neurodegeneration, and disease but remain poorly understood. Here, we report 194,000 single-nucleus microglial transcriptomes and epigenomes across 443 human subjects and diverse Alzheimer's disease (AD) pathological phenotypes. We annotate 12 microglial transcriptional states, including AD-dysregulated homeostatic, inflammatory, and lipid-processing states. We identify 1,542 AD-differentially-expressed genes, including both microglia-state-specific and disease-stage-specific alterations. By integrating epigenomic, transcriptomic, and motif information, we infer upstream regulators of microglial cell states, gene-regulatory networks, enhancer-gene links, and transcription-factor-driven microglial state transitions. We demonstrate that ectopic expression of our predicted homeostatic-state activators induces homeostatic features in human iPSC-derived microglia-like cells, while inhibiting activators of inflammation can block inflammatory progression. Lastly, we pinpoint the expression of AD-risk genes in microglial states and differential expression of AD-risk genes and their regulators during AD progression. Overall, we provide insights underlying microglial states, including state-specific and AD-stage-specific microglial alterations at unprecedented resolution.

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Targeting microglial Cx43 in Alzheimer's disease

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Project description:Alzheimer's disease (AD) remainsis a prevalent major cause of senile dementia without effective therapeutic strategiesy. Although Recent studies highlight the critical role of microglia has been well accepted to play a critical role in AD pathology, particularly in the early stages, this study is the first breakthrough to show, suggesting that modulation of pathological microglial states represents a therapeutic opportunity. Here we provide evidence that microglial connexin 43 (Cx43) hemichannel is the main switch ofs regulate microglial reactivity in the context of AD, as well as a promising hence presenting a potential therapeutic target. We demonstrated a marked increase in Cx43 protein level in the periplaque microglia in the post-mortem tissue from AD patients. In APPswe/PS1dE9 mouse model, we discoveredfound that microglial Cx43 operates as a hemichannel to influence microglial function, which in turn affects in β-amyloid pathology. Ablation of microglial Cx43 hemichannels by genetic knockout screwed microglia to neuroprotective phenotype by promotinges the microglia-plaque interaction while suppressing the neurotoxic microglial signature, and thereby mitigating the progression of AD. Following this lead, wWe developed a novel formulation of small molecule peptide, treatment strategy employing lipid nanoparticle-delivered molecule TAT-Cx43266-283 (TAT-CX43@LNPs), which selectivespecifically targets blocks Cx43 hemichannels, and conducted a. Our preclinical trialstudy that demonstrated its efficacyeffectiveness in delaying and rescuing β-amyloid-related neuropathology and cognitive impairment in AD mice. This study provides strong evidence to progress our novel drug into clinical trials and translate it not only into a therapeutic agent during disease progression but also offer strong preventive benefits when administered early.

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Human Microglial State Dynamics in Alzheimer's Disease Progression

Project description:This SuperSeries is composed of the SubSeries listed below.

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Human Microglial State Dynamics in Alzheimer's Disease Progression [scRNA-seq]

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