| First Author | Jiwaji Z | Year | 2022 |
| Journal | Nat Commun | Volume | 13 |
| Issue | 1 | Pages | 135 |
| PubMed ID | 35013236 | Mgi Jnum | J:321355 |
| Mgi Id | MGI:6857144 | Doi | 10.1038/s41467-021-27702-w |
| Citation | Jiwaji Z, et al. (2022) Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Ass pathology. Nat Commun 13(1):135 |
| abstractText | Alzheimer's disease (AD) alters astrocytes, but the effect of Ass and Tau pathology is poorly understood. TRAP-seq translatome analysis of astrocytes in APP/PS1 ss-amyloidopathy and MAPT(P301S) tauopathy mice revealed that only Ass influenced expression of AD risk genes, but both pathologies precociously induced age-dependent changes, and had distinct but overlapping signatures found in human post-mortem AD astrocytes. Both Ass and Tau pathology induced an astrocyte signature involving repression of bioenergetic and translation machinery, and induction of inflammation pathways plus protein degradation/proteostasis genes, the latter enriched in targets of inflammatory mediator Spi1 and stress-activated cytoprotective Nrf2. Astrocyte-specific Nrf2 expression induced a reactive phenotype which recapitulated elements of this proteostasis signature, reduced Ass deposition and phospho-tau accumulation in their respective models, and rescued brain-wide transcriptional deregulation, cellular pathology, neurodegeneration and behavioural/cognitive deficits. Thus, Ass and Tau induce overlapping astrocyte profiles associated with both deleterious and adaptive-protective signals, the latter of which can slow patho-progression. |
