The Clock Modulator Nobiletin Mitigates Astrogliosis-Associated Neuroinflammation and Disease Hallmarks in an Alzheimer’s Disease Model

Authors

Marvin Wirianto
Chih-Yen Wang
Eunju Kim
Nobuya Koike
Ruben Gomez-Gutierrez
Kazunari Nohara
Gabriel Escobedo
Jong Min Choi
Chorong Han
Kazuhiro Yagita
Sung Yun Jung
Claudio Soto
Hyun Kyoung Lee
Rodrigo Morales
Seung-Hee Yoo
Zheng Chen

Language

English

Publication Date

3-1-2022

Journal

The FASEB Journal

DOI

10.1096/fj.202101633R

PMID

35120261

PMCID

PMC8887996

PubMedCentral® Full Text Version

Post-print

Abstract

Alzheimer's disease (AD) is a devastating neurodegenerative disorder, and there is a pressing need to identify disease-modifying factors and devise interventional strategies. The circadian clock, our intrinsic biological timer, orchestrates various cellular and physiological processes including gene expression, sleep, and neuroinflammation; conversely, circadian dysfunctions are closely associated with and/or contribute to AD hallmarks. We previously reported that the natural compound Nobiletin (NOB) is a clock-enhancing modulator that promotes physiological health and healthy aging. In the current study, we treated the double transgenic AD model mice, APP/PS1, with NOB-containing diets. NOB significantly alleviated β-amyloid burden in both the hippocampus and the cortex, and exhibited a trend to improve cognitive function in these mice. While several systemic parameters for circadian wheel-running activity, sleep, and metabolism were unchanged, NOB treatment showed a marked effect on the expression of clock and clock-controlled AD gene expression in the cortex. In accordance, cortical proteomic profiling demonstrated circadian time-dependent restoration of the protein landscape in APP/PS1 mice treated with NOB. More importantly, we found a potent efficacy of NOB to inhibit proinflammatory cytokine gene expression and inflammasome formation in the cortex, and immunostaining further revealed a specific effect to diminish astrogliosis, but not microgliosis, by NOB in APP/PS1 mice. Together, these results underscore beneficial effects of a clock modulator to mitigate pathological and cognitive hallmarks of AD, and suggest a possible mechanism via suppressing astrogliosis-associated neuroinflammation.

Keywords

Alzheimer Disease, Amyloid beta-Peptides, Animals, Anti-Inflammatory Agents, Cerebral Cortex, Cytokines, Flavones, Gliosis, Hippocampus, Mice, Neuroprotective Agents, Alzheimer's disease, Aβ pathology, circadian clock, neuroinflammation, Nobiletin (NOB), ROR nuclear receptors

Published Open-Access

yes

Recommended Citation

Wirianto, Marvin; Wang, Chih-Yen; Kim, Eunju; et al., "The Clock Modulator Nobiletin Mitigates Astrogliosis-Associated Neuroinflammation and Disease Hallmarks in an Alzheimer’s Disease Model" (2022). Faculty, Staff and Student Publications. 445.
https://digitalcommons.library.tmc.edu/uthshis_docs/445