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.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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 differentiation of familial and sporadic AD patient derived-iPSCs into hippocampal progenitors, CA3 neurons, and cerebral organoids, we found that upregulation of the AP-1 subunit c-JUN triggers decondensation of genomic regions containing TEs. This leads to cytoplasmic accumulation of TE-derived RNA-DNA hybrids, activation of the cGAS-STING cascade, and increased cleaved caspase-3 levels, suggesting initiation of programmed cell death in progenitor cells and neurons. Notably, inhibiting c-JUN effectively blocks all the downstream molecular processes and rescues neuronal death and impaired neurogenesis in the 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.

Neurodegenerative diseases are defined by the propagation of neuroinflammation, driven in part by disease-associated microglia (DAM) that amplify inflammatory signaling and hasten neurodegeneration. Strategies to selectively eliminate DAM to attenuate disease progression remain elusive. Using existing datasets in combination with multiplexed immunofluorescence analysis of post-mortem ALS tissues, we identified the urokinase-type plasminogen activator receptor (uPAR) as a novel surface marker of DAM. uPAR protein is markedly elevated in IBA1⁺/CD68⁺ microglia within ALS-affected regions of both sporadic and familial cases, with negligible expression in unaffected areas or control tissues. These uPAR-high microglia drive neurite retraction in iPSC-derived neurons. To target these cells, we engineered 3rd-generation CAR-T cells expressing an anti-uPAR single-chain variable fragment, enabling specific recognition and elimination of uPAR-expressing microglia. Target specificity was assessed in human microglia C20 cells driven into a pathogenic state by poly(IC) or IFNγ stimulation, which resulted in robust surface uPAR expression alongside phagocytic (CD68⁺) and antigen-presenting (CD80⁺) markers. uPAR-CAR-T cells induced antigen-dependent cytolysis of uPAR-high microglia, reducing their viability by over 80% while sparing resting microglia and neurons in a mixed culture system. These results position uPAR-directed CAR-T cells as a viable immunotherapeutic approach to selectively disrupt disease-amplifying microglial subsets and modify the trajectories of neuroinflammatory diseases.