Astrocytes are implicated in the neuropathology of Alzheimer’s disease (AD) by clustering with other activated inflammatory cells at the sites of amyloid beta (Aβ) deposits formed in the cortex and hippocampus. Astr...Astrocytes are implicated in the neuropathology of Alzheimer’s disease (AD) by clustering with other activated inflammatory cells at the sites of amyloid beta (Aβ) deposits formed in the cortex and hippocampus. Astrocytes are known to contribute to the clearance of Aβ in the AD brain. Also, adult but not neonatal mouse astrocytes are able to clear Aβ deposits from the tissue sections of transgenic AD mice and human brain ex vivo. Because these findings suggest that cultured neonatal astrocytes may not represent a relevant cell for modeling the function of astrocytes in neurodegenerative diseases, we studied whether neonatal and adult astrocytes show different responses in gene expression when exposed to brain sections burdened by deposits of human Aβ. Whole genome microbarrays demonstrated greater alteration of gene expression in adult astrocytes than in neonatal astrocytes. When exposed to Aβ burdened brain sections adult but not neonatal astrocytes up-regulated genes related to peptidase (such as MMP13, MMP12, Phex, Htra1), scavenger receptor (Scara5, Enpp2) and glutathioine transferase (Gsta1, Gsta2, Gclm) activity, suggesting increased ability to degrade and endocytose Aβ peptides and protect against oxidative bursts. Quantitative RT-PCR analysis confirmed the significant alteration in gene expression of key peptidases, scavenger receptors and cholesterol synthesis. Our data suggest that adult astrocytes in culture are more sensitive to disease-relevant stress showing more extensive genetic response compared to neonatal astrocytes. In addition, the identified peptidases and scavenger receptors which increase expression selectively in adult astrocytes suggest their major role in astrocyte-mediated clearance of Aβ deposits in AD.展开更多
文摘Astrocytes are implicated in the neuropathology of Alzheimer’s disease (AD) by clustering with other activated inflammatory cells at the sites of amyloid beta (Aβ) deposits formed in the cortex and hippocampus. Astrocytes are known to contribute to the clearance of Aβ in the AD brain. Also, adult but not neonatal mouse astrocytes are able to clear Aβ deposits from the tissue sections of transgenic AD mice and human brain ex vivo. Because these findings suggest that cultured neonatal astrocytes may not represent a relevant cell for modeling the function of astrocytes in neurodegenerative diseases, we studied whether neonatal and adult astrocytes show different responses in gene expression when exposed to brain sections burdened by deposits of human Aβ. Whole genome microbarrays demonstrated greater alteration of gene expression in adult astrocytes than in neonatal astrocytes. When exposed to Aβ burdened brain sections adult but not neonatal astrocytes up-regulated genes related to peptidase (such as MMP13, MMP12, Phex, Htra1), scavenger receptor (Scara5, Enpp2) and glutathioine transferase (Gsta1, Gsta2, Gclm) activity, suggesting increased ability to degrade and endocytose Aβ peptides and protect against oxidative bursts. Quantitative RT-PCR analysis confirmed the significant alteration in gene expression of key peptidases, scavenger receptors and cholesterol synthesis. Our data suggest that adult astrocytes in culture are more sensitive to disease-relevant stress showing more extensive genetic response compared to neonatal astrocytes. In addition, the identified peptidases and scavenger receptors which increase expression selectively in adult astrocytes suggest their major role in astrocyte-mediated clearance of Aβ deposits in AD.
