The clock modulator Nobiletin mitigates astrogliosis‐associated neuroinflammation and disease hallmarks in an Alzheimer's disease model. Issue 3 (4th February 2022)

• Record Type: Journal Article
• Authors: Wirianto, Marvin; Wang, Chih‐Yen; Kim, Eunju; Koike, Nobuya; Gomez‐Gutierrez, Ruben; Nohara, Kazunari; Escobedo, Gabriel; Choi, Jong Min; Han, Chorong; Yagita, Kazuhiro; Jung, Sung Yun; Soto, Claudio; Lee, Hyun Kyoung; Morales, Rodrigo; Yoo, Seung‐Hee; Chen, Zheng
• Is Part Of: FASEB journal. Volume 36:Issue 3(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-02-04
• Subjects: Alzheimer's disease -- Aβ pathology -- circadian clock -- neuroinflammation -- Nobiletin (NOB) -- ROR nuclear receptors; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.202101633R
• Languages: English
• ISSNs: 0892-6638

Abstract

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.