Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aβ pathology

Alzheimer's disease (AD) alters astrocytes, but the effect of A beta and Tau pathology is poorly understood. TRAP-seq translatome analysis of astrocytes in APP/PS1 beta-amyloidopathy and MAPT(P301S) tauopathy mice revealed that only A beta 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 A beta 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 A beta deposition and phospho-tau accumulation in their respective models, and rescued brain-wide transcriptional deregulation, cellular pathology, neurodegeneration and behavioural/cognitive deficits. Thus, A beta and Tau induce overlapping astrocyte profiles associated with both deleterious and adaptive-protective signals, the latter of which can slow patho-progression.

Automated summary

Alzheimer's disease affects astrocytes, and both A beta and Tau pathology induce changes in astrocytes. A beta mainly influences the expression of AD risk genes, while both pathologies induce age-dependent changes and have overlapping features with astrocytes found in post-mortem AD patients. Both A beta and Tau pathology alter the characteristics of astrocytes, including repression of bioenergetic and translation machinery, induction of inflammation pathways, and expression of protein degradation/proteostasis genes. Astrocyte-specific expression of Nrf2, a protective factor, can recapitulate elements of these astrocyte changes and reduce A beta deposition and phospho-tau accumulation. This Nrf2 expression also improves brain-wide transcriptional deregulation, cellular pathology, neurodegeneration, and behavioral/cognitive deficits.