Cell Autonomous and non-cell autonomous effects of neuronal Bin1 loss in vivo
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA558011 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9879450.fastq.gz | Fastqsanger.gz | |||
| SRR9879460.fastq.gz | Fastqsanger.gz | |||
| SRR9879470.fastq.gz | Fastqsanger.gz | |||
| SRR9879480.fastq.gz | Fastqsanger.gz | |||
| SRR9879490.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: investigate the impact of neuronal Bin1 Loss on surrounding microglia transcriptome. Methods: mRNA profile of microglia cells FACS-sorted from brains of mice homozygous and heterozygous conditional knock-out for Bin1 in excitatory neurons (B6.129S6-Bin1tm2Gcp/J (Bin1flox/flox), <FVB/N-Tg(Thy1-cre)1Vln/J> (Thy1-Cre) ) and Bin1-expressing littermates at 3 month of age had been generated from 10ng of total RNA using SMARTer Ultra Low Input RNA kit v4 (Clontech). The cDNA was amplified by 8 PCR cycles, followed by QC analysis on BioAnalyzer 2100 (Agilent). Sequence libraries were produced from 150pg of cDNA using Nextera XT DNA library kit (Illumina), cleaned up with AMPure XP beads, and QC checked with Caliper LabChip GX. Single-end sequencing data were generated on an Illumina Illumina HiSeq 2500, at a depth of 30 million reads per sample, with read length 50bp.The reads were aligned with the OmicSoft OSA4 to the mouse genome (mm10) and the Ensembl.R84 gene model. Gene counts were estimated using RSEM. Two samples were removed (one sample from WT_Female cohort and one samples from Heterozygote_Male cohort) due to low fraction of uniquely mapped single reads and higher than expected duplication. Of note, these samples with poor technical QC metrics were also clear outliers in PCA. Normalization and differential expression analysis were carried out with the Bioconductor package DESeq2. Differentially expressed genes (DEGs) were defined as having adjpval < 0.05, and |FC| > 1.5. Results: Microglia from homozygous Bin1-cKO mice showed 265 (|FC| > 1.5, FDR <0.05) statistically significant Differentially Expressed Genes (DEGs) in comparison to WT mice. Interestingly, microglia from heterozygous Bin1-cKO mice showed no statistically significant (FDR <0.05) DEGs in comparison to WT mice. Conclusion: neuronal disfunction resulting from Bin1 loss alters gene expression of the surrounding microglia.
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Project description:BIN1 is the most important risk locus for Late Onset Alzheimer's Disease (LOAD), after ApoE. BIN1 AD-associated SNPs correlate with Tau deposition as well as with brain atrophy. Furthermore, the level of neuronal-specific BIN1 isoform 1 protein is decreased in sporadic AD cases in parallel with neuronal loss, despite an overall increase in BIN1 total mRNA. To address the relationship between reduction of BIN1 and neuronal cell loss in the context of Tau pathology, we knocked-down endogenous murine Bin1 via stereotaxic injection of AAV-Bin1 shRNA in the hippocampus of mice expressing Tau P301S (PS19). We observed a statistically significant reduction in the number of neurons in the hippocampus of mice injected with AAV-Bin1 shRNA in comparison with mice injected with AAV control. To investigate whether neuronal loss is due to deletion of Bin1 selectively in neurons in presence Tau P301S, we bred Bin1flox/flox with Thy1-Cre and subsequently with PS19 mice. Mice lacking neuronal Bin1 and expressing Tau P301S showed increased mortality, without increased neuropathology, when compared to neuronal Bin1 and Tau P301S-expressing mice. The loss of Bin1 isoform 1 resulted in reduced excitability in primary neurons in vitro, reduced neuronal c-fos expression as well as in altered microglia transcriptome in vivo. Taken together, our data suggest that the contribution of genetic variation in BIN1 locus to AD risk could result from a cell-autonomous reduction of neuronal excitability due to Bin1 decrease, exacerbated by the presence of aggregated Tau, coupled with a non-cell autonomous microglia activation.
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