This study investigates the role of astrocytic autophagy in Alzheimer's disease (AD). Astrocytes, a key cell type in the brain, transform into reactive astrocytes in response to toxic proteins like amyloid beta (Aβ) in AD. The study aims to determine whether Aβ-induced proteotoxic stress affects autophagy gene expression and autophagic flux in astrocytes, and how these changes are involved in Aβ clearance in AD animal models. **Methods:** - **RNA Sequencing (RNA-seq):** Whole RNA sequencing was performed to detect gene expression patterns in Aβ-treated human astrocytes over time. - **Gene Silencing and Overexpression:** AAVs expressing shRNAs for *MAP1LC3B/LC3B* and *Sequestosome1* (*SQSTM1*) were developed to silence these genes in astrocytes. Overexpression of *LC3B* was also tested in AD mice. - **Neuropathological and Behavioral Assays:** Confocal microscopy and transmission electron microscopy (TEM) were used to observe neuropathological alterations, and behavioral tests (novel object recognition and place recognition) were conducted to assess cognitive function. **Results:** - **Aβ-Induced Autophagy:** Aβ transiently induces *LC3B* gene expression and prolonged *SQSTM1* transcription. Astrocytic autophagy is crucial for Aβ clearance and maintaining cognitive function. - **Autophagy Inhibition:** Pharmacological inhibition of autophagy exacerbates mitochondrial dysfunction and oxidative stress in astrocytes. Knockdown of *LC3B* and *SQSTM1* increases Aβ plaque formation and astrocytic markers, reducing neuronal markers and cognitive function. Conversely, overexpression of *LC3B* reduces Aβ aggregates in AD mice. - **Clinical Relevance:** Increased *LC3B* and *SQSTM1* protein levels are observed in the hippocampus of AD patients, suggesting that astrocytic autophagy dysfunction is a significant factor in AD. **Conclusions:** The study demonstrates that Aβ-induced astrocytic autophagy is essential for Aβ clearance and maintaining cognitive function in AD. This process involves the activation of the urea cycle and putrescine degradation pathway, which helps detoxify Aβ. The findings highlight the importance of astrocytic autophagy in AD pathogenesis and provide insights into potential therapeutic targets.This study investigates the role of astrocytic autophagy in Alzheimer's disease (AD). Astrocytes, a key cell type in the brain, transform into reactive astrocytes in response to toxic proteins like amyloid beta (Aβ) in AD. The study aims to determine whether Aβ-induced proteotoxic stress affects autophagy gene expression and autophagic flux in astrocytes, and how these changes are involved in Aβ clearance in AD animal models. **Methods:** - **RNA Sequencing (RNA-seq):** Whole RNA sequencing was performed to detect gene expression patterns in Aβ-treated human astrocytes over time. - **Gene Silencing and Overexpression:** AAVs expressing shRNAs for *MAP1LC3B/LC3B* and *Sequestosome1* (*SQSTM1*) were developed to silence these genes in astrocytes. Overexpression of *LC3B* was also tested in AD mice. - **Neuropathological and Behavioral Assays:** Confocal microscopy and transmission electron microscopy (TEM) were used to observe neuropathological alterations, and behavioral tests (novel object recognition and place recognition) were conducted to assess cognitive function. **Results:** - **Aβ-Induced Autophagy:** Aβ transiently induces *LC3B* gene expression and prolonged *SQSTM1* transcription. Astrocytic autophagy is crucial for Aβ clearance and maintaining cognitive function. - **Autophagy Inhibition:** Pharmacological inhibition of autophagy exacerbates mitochondrial dysfunction and oxidative stress in astrocytes. Knockdown of *LC3B* and *SQSTM1* increases Aβ plaque formation and astrocytic markers, reducing neuronal markers and cognitive function. Conversely, overexpression of *LC3B* reduces Aβ aggregates in AD mice. - **Clinical Relevance:** Increased *LC3B* and *SQSTM1* protein levels are observed in the hippocampus of AD patients, suggesting that astrocytic autophagy dysfunction is a significant factor in AD. **Conclusions:** The study demonstrates that Aβ-induced astrocytic autophagy is essential for Aβ clearance and maintaining cognitive function in AD. This process involves the activation of the urea cycle and putrescine degradation pathway, which helps detoxify Aβ. The findings highlight the importance of astrocytic autophagy in AD pathogenesis and provide insights into potential therapeutic targets.