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

• DOI: 10.1096/fj.202101633r
• Publication Date: 2022-02-04T17:45:44Z
• Authors: Marvin Wirianto; Chih‐Yen Wang; Eunju Kim; Nobuya Koike; Ruben Gomez‐Gutie...; 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
• Keywords: Astrogliosis; Proinflammatory cytokine

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