Astrocytes deficient in circadian clock gene Bmal1 show enhanced activation responses to amyloid-beta pathology without changing plaque burden

Celia A Mckee,Takashi Saito,Erik S Musiek,Jiyeon Lee,Takaomi Saido,Yuqi Cai

doi:10.1038/s41598-022-05862-z

Abstract

An emerging link between circadian clock function and neurodegeneration has indicated a critical role for the molecular clock in brain health. We previously reported that deletion of the core circadian clock gene Bmal1 abrogates clock function and induces cell-autonomous astrocyte activation. Regulation of astrocyte activation has important implications for protein aggregation, inflammation, and neuronal survival in neurodegenerative conditions such as Alzheimer's disease (AD). Here, we investigated how astrocyte activation induced by Bmal1 deletion regulates astrocyte gene expression, amyloid-beta (Aβ) plaque-associated activation, and plaque deposition. To address these questions, we crossed astrocyte-specific Bmal1 knockout mice (Aldh1l1-CreERT2;Bmal1fl/fl, termed BMAL1 aKO), to the APP/PS1-21 and the APPNL-G-F models of Aβ accumulation. Transcriptomic profiling showed that BMAL1 aKO induced a unique transcriptional profile affecting genes involved in both the generation and elimination of Aβ. BMAL1 aKO mice showed exacerbated astrocyte activation around Aβ plaques and altered gene expression. However, this astrogliosis did not affect plaque accumulation or neuronal dystrophy in either model. Our results demonstrate that the striking astrocyte activation induced by Bmal1 knockout does not influence Aβ deposition, which indicates that the effect of astrocyte activation on plaque pathology in general is highly dependent on the molecular mechanism of activation.

Highlights

An emerging link between circadian clock function and neurodegeneration has indicated a critical role for the molecular clock in brain health
To understand how Bmal1-depleted astrocytes behave in the context of Aβ pathology, we examined astrocyte activation in the cortex of BMAL1 aKO mice crossed to the APP/PS1-21 model of Aβ-amyloidosis (Aldh1l1CreERT2;Bmal1fl/fl;APP/PS1-21)
It has been reported that disease-associated astrocytes (DAAs) in 5xFAD mice have a transcriptional profile that diverges from GFAP-expressing wildtype a strocytes[38]

Summary

Introduction

An emerging link between circadian clock function and neurodegeneration has indicated a critical role for the molecular clock in brain health. We investigated how astrocyte activation induced by Bmal[1] deletion regulates astrocyte gene expression, amyloid-beta (Aβ) plaque-associated activation, and plaque deposition. BMAL1 aKO mice showed exacerbated astrocyte activation around Aβ plaques and altered gene expression This astrogliosis did not affect plaque accumulation or neuronal dystrophy in either model. The influence of astrocyte activation in AD still remains to be elucidated: it is unclear whether astrocyte activation primarily exacerbates neuroinflammation and hastens pathogenesis, or whether it tips the balance towards beneficial functions in clearing Aβ and aiding neuronal survival[10] These opposing possibilities are reflected in recent literature targeting astrocytes in AD. Unraveling the connection between clock-controlled gene expression and AD progression may reveal pathways amenable to targeting for AD treatment

Methods

Results

Conclusion