Abstract
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 MAPTP301S 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.
Highlights
Alzheimer’s disease (AD) alters astrocytes, but the effect of Aß and Tau pathology is poorly understood
To determine whether gene expression changes evident in latestage MAPTP301S and APPswe/PS1dE9 mice13 (APP/PS1) astrocytes were beginning to occur at the earlier stage, we took the groups of genes induced >2
The MAPTP301S tauopathy mouse model expresses mutant Tau-P301S in neurons[10]. This leads to the accumulation of hyperphosphorylated filamentous tau, driving progressive neurodegeneration in the spinal cord and upper cortical layers, with physical deterioration of the mouse from around 5 months[10,11,12]
Summary
Alzheimer’s disease (AD) alters astrocytes, but the effect of Aß and Tau pathology is poorly understood. Despite the catch-all term of ‘astrogliosis’ it is becoming clear that the properties of ‘reactive astrocytes’ vary substantially according to the upstream trigger and evolve substantially during patho-progression, reflecting the diversity of extracellular signals being received[9].While some signals can induce deleterious effects, others may trigger adaptive-protective consequences, and so a reactive astrocyte phenotype cannot be predicted from simple marker gene expression (e.g. Gfap). Another unanswered question is how the two aspects of AD-associated proteopathy, Aß and Tau, influence astrocytes. To determine whether gene expression changes evident in latestage MAPTP301S and APP/PS1 astrocytes were beginning to occur at the earlier stage, we took the groups of genes induced >2-
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