Cx43 in Cdh5+ cells maintains blood-brain barrier integrity by NAD+ during aging
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA723191 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14279707_1.fastq.gz | Fastqsanger.gz | |||
| SRR14279707_2.fastq.gz | Fastqsanger.gz | |||
| SRR14279708_1.fastq.gz | Fastqsanger.gz | |||
| SRR14279708_2.fastq.gz | Fastqsanger.gz | |||
| SRR14279709_1.fastq.gz | Fastqsanger.gz |
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Project description:Blood-brain barrier (BBB) function deteriorates during aging, contributing to cognitive impairment and neurodegeneration. It is unclear what drives BBB leakage in aging and how it can be prevented. Using single-nucleus transcriptomics, we identified decreased connexin 43 (CX43) expression in Cadherin-5+ (Cdh5+) cerebral vascular cells in naturally aging mice and confirmed it in human brain samples. Global or Cdh5+ cell-specific CX43 deletion in mice exacerbated BBB dysfunction during aging. The CX43-dependent effect was not due to its canonical gap junction function but was associated with reduced NAD+ levels and mitochondrial dysfunction through NAD+-dependent sirtuin 3. CX43 interacts with and negatively regulates poly (ADP-ribose) polymerase 1 (PARP1). Pharmacologic inhibition of PARP1 by olaparib or nicotinamide mononucleotide supplementation rescued NAD+ levels and alleviated aging-associated BBB leakage. These findings establish the endothelial CX43-PARP1-NAD+ pathway’s role in vascular aging and identify a potential therapeutic strategy to combat aging-associated BBB leakage with neuroprotective implications.
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Project description:Cy3-labeled cDNA from brains of neonatal C57BL Cx43 null, Cx43 heterozygous and Cx32 null mice were compared among themselves and to Cy3-labeled cDNA from brains of neonatal C57BL wildtype mice through Cy5-labeled sample reference prepared at once for the entire experiment from aorta, brain, heart, kidney, liver, lung, ovary/testicles, spleen, and stomach - equal amounts from adult male and female C57BL mice.
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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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Project description:The main objective of the present report was to unravel the Cx43-interaction network in the heart, and to establish the impact of heart ischemia and I/R upon these interactions. In order to characterize the cardiac Cx43 interactome under ischemia and I/R, a quantitative proteomic analysis was performed, through the combination of immunopurification of endogenous Cx43 (Cx43 IP) and identification of its binding partners with the SWATH-MS approach, using rat hearts maintained in a Langendorff apparatus. In the present approach 444 proteins were identified, including proteins identified based on a single peptide (supplementary table I). From these 444 proteins, 299 (approximately 67 % of the entire dataset) were quantified and compared between the various experimental conditions (including non-specific binding to control IP samples). These 299 proteins were further evaluated by a series of complementary analysis to deciphering the truly interactors of Cx43. According with this evaluation, 236 out of the 299 quantified proteins were considered as putative Cx43 interacting partners in the cardiac context presented The results obtained in this study demonstrate that Cx43 mainly interacts with proteins related with metabolism, signaling and trafficking, and that this interactome can be differentially modulated in diseased hearts. Our results shed new light upon the understanding of Cx43 functions in the heart, both in health and disease, which ultimately may lead to the establishment of new therapeutic targets to modulate cardiac homeostasis.
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