Distinct Flower signaling domains orchestrate cellular fitness via secreted vesicles in Aβ-induced neurodegeneration

Chang, H.-F.; Tu, S.-M.; Lin, C.-H.; Liu, Y.; Hohneck, J.; Jung, M.; Clemenz, A.; Rother, S.; Schirra, C.; Schwarz, Y.; Krause, E.; Schulz-Schaeffer, W. J.; Flockerzi, V.; Yao, C.-K.

doi:10.1101/2025.08.08.669265

bioRxiv · 10.1101/2025.08.08.669265

Distinct Flower signaling domains orchestrate cellular fitness via secreted vesicles in Aβ-induced neurodegeneration

Chang, H.-F.·Tu, S.-M.·Lin, C.-H.·Liu, Y.·Hohneck, J.·Jung, M.·Clemenz, A.·Rother, S.·Schirra, C.·Schwarz, Y.·Krause, E.·Schulz-Schaeffer, W. J.·Flockerzi, V.·Yao, C.-K.

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Abstract

Cellular fitness surveillance preserves tissue integrity, yet its regulation within the mammalian brain remains poorly understood. We identify a bifurcated mechanism in the transmembrane protein Flower--encoding both survival-promoting ("win") and apoptosis-inducing ("lose") isoforms. We demonstrate that astrocytes secrete specialized extracellular vesicles (EVs), termed "fitness vesicles," carrying Flower to facilitate competitive selection across distal cell populations. The N-terminal Flower domain acts extrinsically via these EVs to drive the elimination of less-fit neighbors. Conversely, the "win"-specific C-terminal domain functions as a cell-intrinsic module; it translocates to the nucleus under stress to repress Caspase-3 and provide resilience. In Alzheimers disease (AD) models and human AD brains, Flower-positive astrocytes accumulate around amyloid-{beta} (A{beta}) plaques. Under A{beta} stress, the "win" isoform reprograms astrocytes toward a neuroprotective state that enhances plaque clearance while ensuring cell-intrinsic survival. Our findings reveal how Flower couples long-range, EV-mediated cellular selection with cell-autonomous protection to coordinate astrocyte quality control and tissue resilience in neurodegeneration.

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Chang, H.-F., Tu, S.-M., Lin, C.-H., Liu, Y., Hohneck, J., Jung, M., Clemenz, A., Rother, S., Schirra, C., Schwarz, Y., Krause, E., Schulz-Schaeffer, W. J., Flockerzi, V., Yao, C.-K.. 2025-08-12. Distinct Flower signaling domains orchestrate cellular fitness via secreted vesicles in Aβ-induced neurodegeneration. https://doi.org/10.1101/2025.08.08.669265

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