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The clock modulator Nobiletin mitigates astrogliosis‐associated neuroinflammation and disease hallmarks in an Alzheimer’s disease model
Author(s) -
Wirianto Marvin,
Wang ChihYen,
Kim Eunju,
Koike Nobuya,
GomezGutierrez Ruben,
Nohara Kazunari,
Escobedo Gabriel,
Choi Jong Min,
Han Chorong,
Yagita Kazuhiro,
Jung Sung Yun,
Soto Claudio,
Lee Hyun Kyoung,
Morales Rodrigo,
Yoo SeungHee,
Chen Zheng
Publication year - 2022
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202101633r
Subject(s) - astrogliosis , neuroinflammation , neuroscience , circadian rhythm , neurodegeneration , proinflammatory cytokine , clock , medicine , circadian clock , biology , inflammation , disease , central nervous system
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.