| First Author | Kim S | Year | 2024 |
| Journal | Mol Neurodegener | Volume | 19 |
| Issue | 1 | Pages | 55 |
| PubMed ID | 39044253 | Mgi Jnum | J:358513 |
| Mgi Id | MGI:7704599 | Doi | 10.1186/s13024-024-00740-w |
| Citation | Kim S, et al. (2024) Astrocytic autophagy plasticity modulates Abeta clearance and cognitive function in Alzheimer's disease. Mol Neurodegener 19(1):55 |
| abstractText | BACKGROUND: Astrocytes, one of the most resilient cells in the brain, transform into reactive astrocytes in response to toxic proteins such as amyloid beta (Abeta) in Alzheimer's disease (AD). However, reactive astrocyte-mediated non-cell autonomous neuropathological mechanism is not fully understood yet. We aimed our study to find out whether Abeta-induced proteotoxic stress affects the expression of autophagy genes and the modulation of autophagic flux in astrocytes, and if yes, how Abeta-induced autophagy-associated genes are involved Abeta clearance in astrocytes of animal model of AD. METHODS: Whole RNA sequencing (RNA-seq) was performed to detect gene expression patterns in Abeta-treated human astrocytes in a time-dependent manner. To verify the role of astrocytic autophagy in an AD mouse model, we developed AAVs expressing shRNAs for MAP1LC3B/LC3B (LC3B) and Sequestosome1 (SQSTM1) based on AAV-R-CREon vector, which is a Cre recombinase-dependent gene-silencing system. Also, the effect of astrocyte-specific overexpression of LC3B on the neuropathology in AD (APP/PS1) mice was determined. Neuropathological alterations of AD mice with astrocytic autophagy dysfunction were observed by confocal microscopy and transmission electron microscope (TEM). Behavioral changes of mice were examined through novel object recognition test (NOR) and novel object place recognition test (NOPR). RESULTS: Here, we show that astrocytes, unlike neurons, undergo plastic changes in autophagic processes to remove Abeta. Abeta transiently induces expression of LC3B gene and turns on a prolonged transcription of SQSTM1 gene. The Abeta-induced astrocytic autophagy accelerates urea cycle and putrescine degradation pathway. Pharmacological inhibition of autophagy exacerbates mitochondrial dysfunction and oxidative stress in astrocytes. Astrocyte-specific knockdown of LC3B and SQSTM1 significantly increases Abeta plaque formation and GFAP-positive astrocytes in APP/PS1 mice, along with a significant reduction of neuronal marker and cognitive function. In contrast, astrocyte-specific overexpression of LC3B reduced Abeta aggregates in the brain of APP/PS1 mice. An increase of LC3B and SQSTM1 protein is found in astrocytes of the hippocampus in AD patients. CONCLUSIONS: Taken together, our data indicates that Abeta-induced astrocytic autophagic plasticity is an important cellular event to modulate Abeta clearance and maintain cognitive function in AD mice. |
