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Running title: Astrocyte senescence leads to neurotoxicity 2 ABBREVIATIONS: AD, Alzheimer's disease; Aβ, amyloid-β; SASP, senescence-associated secretory phenotype; CS, cellular senescence; AS, astrocyte senescence; NF-κB, kappa-lightchain-enhancer of activated B cells; IL-6, interleuken-6; TGF β1, transforming growth factor β; PBS, phosphate buffered saline; PDTC, pyrrolidinedithiocarbamic acid ammonium salt; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; WT, wild-type; Real-time polymerase chain reaction (RT-PCR) mRNA, messenger RNA; ELISA, enzyme-linked immunosorbent assay; WB, western blot; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; VEGF, vascular endothelial growth factor; BDNF, brain-derived neurotrophic factor; GFAP, glial fibrillary acidic protein 3 ABSTRACT: Alterations in astrocyte function such as a pro-inflammatory phenotype are associated with Alzheimer's disease (AD). We had shown impairments in the ability of aged astrocytes isolated from 5xFAD mice to clear and uptake amyloid-β (Aβ) as well as to support neuronal growth. Senescent cells accumulate with age and exhibit a senescence-associated secretory phenotype, which includes secretion of pro-inflammatory cytokines. In this study, we predicted that with age, astrocytes in 5xFAD mice would exhibit a cellular senescence phenotype that could promote neurodegeneration. We found an age-dependent increase in senescent astrocytes adjacent to Aβ plaques in 5xFAD mice. Inhibition of nuclear factor kappalight-chain-enhancer of activated B cells reduced interelukin-6 secretion by senescent astrocytes and resulted in improved neuronal support. Moreover, senescent astrocytes exhibited an increase in the induction of the TGF-β1-SMAD2/3 pathway, and inhibition of this pathway resulted in a reduction of cellular senescence. We also discovered that soluble Aβ42 induced astrocyte senescence in young naïve mice in a SMAD2/3-dependent manner. Our results suggest an important role of astrocyte senescence in AD and its role in mediating the neurotoxicity properties of astrocytes in AD and related neurodegenerative diseases.