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

Flower isoforms regulate cellular fitness and are implicated in neurodegeneration and tumor progression, yet their mechanisms remain unclear. Using Flower knockout mice, we identify the N- and C-terminal domains as distinct signaling modules: the C-terminus promotes survival of fitter ( winner) cells via intrinsic signaling, while the N-terminus induces apoptosis of neighboring less-fit ( loser) cells via extrinsic signaling. Notably, Flower signaling operates via secreted extracellular vesicles (EVs), with the win isoform exhibiting [~]25-fold higher secretion than the lose, thereby facilitating intercellular fitness selection. In Alzheimers disease human brain tissue and APP transgenic mice, win isoforms are enriched in astrocytes near amyloid-{beta} plaques, suggesting localized fitness surveillance. In cortical neuron-glia cultures, overexpression of the win isoform or its C-terminal domain enhances astrocytic A{beta} clearance and protects neurons from A{beta} toxicity. These findings uncover a novel Flower signaling pathway controlling cell death, providing new insights into EV-mediated communication with therapeutic potential in neurodegeneration.