title: Immunization with Bacillus Calmette-Guérin (BCG) alleviates neuroinflammation and cognitive deficits in APP/PS1 mice via the recruitment of inflammation-resolving monocytes to the brain.
abstract: The immune system plays a crucial role in the progression of Alzheimer's disease (AD). Recently, immune-dependent cascade induced by systemic immune activation has been verified to play a beneficial role in AD mouse models. Here, we tested whether Bacillus Calmette-Guérin (BCG) immunization alters AD pathology and cognitive dysfunction in APP/PS1 AD mouse model, and with 4Aβ1-15 vaccination as positive control. It was found that BCG treatment reversed the cognitive decline to the extent observed in 4Aβ1-15 group, but did not reduce the β-amyloid (Aβ) burden in the brain. Then, we demonstrated the enhanced recruitment of inflammation-resolving monocytes across the choroid plexus and perivascular spaces to cerebral sites of plaque pathology in APP/PS1 mice immunized with BCG. Furthermore, elevated splenocyte Foxp3+regulatory T cell levels in the control APP/PS1 mice were down-regulated back to the wild-type (WT) levels by BCG treatment but not 4Aβ1-15 vaccination. In addition, BCG treatment induced the production of more circulating interferon (IFN)-γ than the controls and 4Aβ1-15 vaccination. Though the similar reductions in brain levels of pro-inflammatory cytokines were observed in the BCG and 4Aβ1-15 groups compared to the controls, only BCG had the great effect in upregulating cerebral anti-inflammatory cytokine levels as well as elevating the expression of neurotrophic factors in the brain of APP/PS1 mice. Thus, it is suggested that BCG exerts a beneficial immunomodulatory effect in APP/PS1 mice through mitigation of systemic immune suppression, induction of IFN-γ response and alleviation of the neuroinflammatory response.
authors.affiliation: Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, #74, Zhongshan No. 2 Road, Guangzhou 510080, China; Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, #74, Zhongshan No. 2 Road, Guangzhou 510080, China.
authors.forename: Zejie
authors.initials: Z
authors.lastname: Zuo
authors.affiliation: Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, #74, Zhongshan No. 2 Road, Guangzhou 510080, China; Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, #74, Zhongshan No. 2 Road, Guangzhou 510080, China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Qi
authors.affiliation: Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, #74, Zhongshan No. 2 Road, Guangzhou 510080, China; Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, #74, Zhongshan No. 2 Road, Guangzhou 510080, China.
authors.forename: Junhua
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, #74, Zhongshan No. 2 Road, Guangzhou 510080, China; Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, #74, Zhongshan No. 2 Road, Guangzhou 510080, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, #74, Zhongshan No. 2 Road, Guangzhou 510080, China; Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, #74, Zhongshan No. 2 Road, Guangzhou 510080, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, #74, Zhongshan No. 2 Road, Guangzhou 510080, China; Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, #74, Zhongshan No. 2 Road, Guangzhou 510080, China.
authors.forename: Yaru
authors.initials: Y
authors.lastname: Wen
authors.affiliation: Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, #74, Zhongshan No. 2 Road, Guangzhou 510080, China; Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, #74, Zhongshan No. 2 Road, Guangzhou 510080, China.
authors.forename: Qunfang
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, #74, Zhongshan No. 2 Road, Guangzhou 510080, China; Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, #74, Zhongshan No. 2 Road, Guangzhou 510080, China.
authors.forename: Juntao
authors.initials: J
authors.lastname: Zou
authors.affiliation: Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, #74, Zhongshan No. 2 Road, Guangzhou 510080, China; Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, #74, Zhongshan No. 2 Road, Guangzhou 510080, China.
authors.forename: Kaihua
authors.initials: K
authors.lastname: Guo
authors.affiliation: Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, #74, Zhongshan No. 2 Road, Guangzhou 510080, China; Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, #74, Zhongshan No. 2 Road, Guangzhou 510080, China. Electronic address: yao.zb@163.com.
authors.forename: Zhi Bin
authors.initials: ZB
authors.lastname: Yao
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000276:immunology; D000818:Animals; D001500:BCG Vaccine / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005911:Gliosis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D010446:Peptide Fragments / Q000276:immunology; D013154:Spleen / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology
chemical_list: D016229:Amyloid beta-Peptides; D001500:BCG Vaccine; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C556062:IL10 protein, mouse; D010446:Peptide Fragments; C480626:amyloid beta-protein (1-15); D016753:Interleukin-10
keywords: AD; Anti-inflammation; BCG; IFN-γ; Monocytes; Vaccination