JUN upregulation drives aberrant transposable element mobilization, associated innate immune response, and impaired neurogenesis in Alzheimer’s disease

Adult neurogenic decline, inflammation, and neurodegeneration are phenotypic hallmarks of Alzheimer’s disease (AD). Mobilization of transposable elements (TEs) in heterochromatic regions was recently reported in AD, but the underlying mechanisms are still underappreciated. Combining functional genomics with the differentiation of familial and sporadic AD patient derived-iPSCs into hippocampal progenitors, CA3 neurons, and cerebral organoids, we found that the upregulation of the AP-1 subunit, c-Jun, triggers decondensation of genomic regions containing TEs. This leads to the cytoplasmic accumulation of HERVK-derived RNA-DNA hybrids, the activation of the cGAS-STING cascade, and increased levels of cleaved caspase-3, suggesting the initiation of programmed cell death in AD progenitors and neurons. Notably, inhibiting c-Jun effectively blocks all these downstream molecular processes and rescues neuronal death and the impaired neurogenesis phenotype in AD progenitors. Our findings open new avenues for identifying therapeutic strategies and biomarkers to counteract disease progression and diagnose AD in the early, pre-symptomatic stages.


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Three conditions: Familial AD, Sporadic AD, and Control. 3 biological replicates per condition (except for the Sporadic AD, for which we only had two lines) and multiple technical replicates per biological replicates.Specifically we used 6 Alzheimer's disease patient iPSC lines (3 familiar alzheimer's disease ones and 2 sporadic Alzheimer's disease ones) and 3 control lines from healthy donor.Two technical replicates per each biological replicate for the NGS experiments: ATAC-seq, RNA-seq three technical replicates for other experiments.The biological replicates always included males and females, of comparable age ranges.One of the Familial AD pair was isogenic.The choses sample size (5 AD lines and 3 CTRL lines) guaranteed sufficient statistical power to replicate the findings biologically at least three times (standard in the field) and detect differentially expressed genes using DESEQ2.It is also worth mentioning that the sample size included ISOGENIC LINES.
Data exclusions We excluded one FAD replicate from one of the RNA-seq analysis because of poor data quality.
Replication 2 biological replicates per condition: 5 Alzheimer's disease patient iPSC lines (3 familiar alzheimer's disease ones and 2 sporadic Alzheimer's disease ones) vs 3 control lines from healthy donor.Two technical replicates per each biological replicate for the NGS experiments: ATAC-seq, RNA-seq three technical replicates for others experiments.The biological replicates included male and female, comparable age ranges.All the replications were successful.
Randomization To avoid batch effect, the samples from different conditions (controls, patients) were always processed in the same batch Blinding N/A.It was not necessary as we are working with cell lines, that were identified as either Alzheimer or Healthy, and all the cell lines were always processed together in all experiments.
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