The clock modulator Nobiletin mitigates astrogliosis‐associated neuroinflammation and disease hallmarks in an Alzheimer’s disease model

• Published in: The FASEB journal Vol. 36; no. 3; pp. e22186 - n/a
• Main 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
• Format: Journal Article
• Language: English
• Published: United States 01.03.2022
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Aβ pathology; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; circadian clock; Cytokines - genetics; Cytokines - metabolism; Flavones - pharmacology; Flavones - therapeutic use; Gliosis - drug therapy; Gliosis - metabolism; Hippocampus - drug effects; Hippocampus - metabolism; Mice; neuroinflammation; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Nobiletin (NOB); ROR nuclear receptors; Aβ pathology; Nobiletin (NOB); neuroinflammation; Alzheimer's disease; circadian clock; ROR nuclear receptors
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.202101633R

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.