Protective Effects of Rivaroxaban on White Matter Integrity and Remyelination in a Mouse Model of Alzheimer’s Disease Combined with Cerebral Hypoperfusion

Article type: Research Article

Authors: Bian, Zhihong^a | Hu, Xinran^a | Liu, Xia^b | Yu, Haibo^a | Bian, Yuting^a | Sun, Hongming^a | Fukui, Yusuke^a | Morihara, Ryuta^a | Ishiura, Hiroyuki^a | Yamashita, Toru^{a; *}

Affiliations: [a] Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama, Japan | [b] Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Correspondence: [*] Correspondence to: Dr. Toru Yamashita, Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. Tel.: +1 81 86 235 7365; Fax: +81 86 235 7368; E-mail: toruyamashita@okayama-u.ac.jp.

Abstract: Background:Alzheimer’s disease (AD) is characterized by cognitive dysfunction and memory loss that is accompanied by pathological changes to white matter. Some clinical and animal research revealed that AD combined with chronic cerebral hypoperfusion (CCH) exacerbates AD progression by inducing blood-brain barrier dysfunction and fibrinogen deposition. Rivaroxaban, an anticoagulant, has been shown to reduce the rates of dementia in atrial fibrillation patients, but its effects on white matter and the underlying mechanisms are unclear. Objective:The main purpose of this study was to explore the therapeutic effect of rivaroxaban on the white matter of AD+CCH mice. Methods:In this study, the therapeutic effects of rivaroxaban on white matter in a mouse AD+CCH model were investigated to explore the potential mechanisms involving fibrinogen deposition, inflammation, and oxidative stress on remyelination in white matter. Results:The results indicate that rivaroxaban significantly attenuated fibrinogen deposition, fibrinogen-related microglia activation, oxidative stress, and enhanced demyelination in AD+CCH mice, leading to improved white matter integrity, reduced axonal damage, and restored myelin loss. Conclusions:These findings suggest that long-term administration of rivaroxaban might reduce the risk of dementia.

Keywords: Alzheimer’s disease, cerebral amyloid angiopathy, chronic cerebral hypoperfusion, rivaroxaban, white matter

DOI: 10.3233/JAD-230413

Journal: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 609-622, 2023