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

Zuo, Zejie; Qi, Fangfang; Yang, Jiliang; Wang, Xiao; Wu, Yingying; Wen, Yaru; Yuan, Qing; Zou, Juntao; Ke, Guo; Yao, Zhi

doi:10.1016/j.nbd.2017.02.001

Cited by 53 publications

(44 citation statements)

References 67 publications

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“…Tregs are CD4 positive T-lymphocyte subsets that can maintain peripheral immune tolerance [25,46,47]. Previous and our studies have reported elevated Treg counts in AD patients and an Aβ-driven AD mouse model [17,27,48], supporting the notion that aging and AD are characterized by immune tolerance and/or immune senescence [13,49]. In the present study, the systemic reduction in peripheral Tregs after the IIV treatment was associated with the mitigation of the disease pathology and cognitive impairments.…”

Section: Discussionsupporting

confidence: 84%

“…We previously reported that BCG vaccination improved cognitive deficits in AD, but without Aβ plaque clearance [17]. To determine the effect of IIV on Aβ pathology in APP/PS1 mice, we examined the area and percentage of Aβ burden in cerebral sections.…”

Section: Iiv Treatment Attenuates the Cerebral Aβ Plaque Burden In Apmentioning

confidence: 99%

“…Other studies have suggested that systemic immunosuppression, which has shown some effectiveness, might impair the normal immunity required to fight cerebral pathology due to the lack of immune surveillance function in AD [13][14][15][16]. Our previous study showed that Bacillus Calmette-Guerin (BCG)-induced effective immunomodulatory effects, promoted neurogenesis under physiological conditions, mitigated systemic immune suppression, and improved cognitive deficits in AD, without Aβ plaque clearance [17]. However, whether multiple early vaccinations with inactivated influenza vaccine (IIV) could relieve the brain pathology and memory deficits in AD remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Influenza vaccination in early Alzheimer’s disease rescues amyloidosis and ameliorates cognitive deficits in APP/PS1 mice by inhibiting regulatory T cells

Yang

Xing

et al. 2020

J Neuroinflammation

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Background: Alzheimer's disease (AD) is a neurodegenerative disorder strongly correlated with a dysfunctional immune system. Our previous results demonstrated that inactivated influenza vaccine (IIV) facilitates hippocampal neurogenesis and blocks lipopolysaccharide (LPS)-induced cognitive impairment. However, whether IIV improves cognitive deficits in an AD mouse model remains unclear. In addition, early interventions in AD have been encouraged in recent years. Here, we investigated whether IIV immunization at the preclinical stage of AD alters the brain pathology and cognitive deficits in an APP/ PS1 mouse model. Methods: We assessed spatial learning and memory using Morris water maze (MWM). The brain β-amyloid (Aβ) plaque burden and activated microglia were investigated by immunohistochemistry. Furthermore, flow cytometry was utilized to analyze the proportions of Treg cells in the spleen. A cytokine antibody array was performed to measure the alteration of cytokines in the brain and peripheral immune system. Results: Five IIV immunizations activated microglia, reduced the Aβ burden and improved the cognitive impairment. Simultaneously, the IIV-induced immune response broke peripheral immunosuppression by reducing Foxp3 + regulatory T cell (Treg) activities, whereas the restoration of Treg level in the periphery using all-trans retinoic acid (ATRA) blunted the protective effects of IIV on Aβ burden and cognitive functions. Interestingly, IIV immunization might increase proinflammatory and anti-inflammatory cytokine expression in the brain of APP/PS1 mice, enhanced microglial activation, and enhanced the clustering and phagocytosis of Aβ, thereby creating new homeostasis in the disordered immune microenvironment. Conclusions: Altogether, our results suggest that early multiple IIV immunizations exert a beneficial immunomodulatory effect in APP/PS1 mice by breaking Treg-mediated systemic immune tolerance, maintaining the activation of microglia and removing of Aβ plaques, eventually improving cognitive deficits.

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Section: Discussionsupporting

confidence: 84%

Section: Iiv Treatment Attenuates the Cerebral Aβ Plaque Burden In Apmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Influenza vaccination in early Alzheimer’s disease rescues amyloidosis and ameliorates cognitive deficits in APP/PS1 mice by inhibiting regulatory T cells

Yang

Xing

et al. 2020

J Neuroinflammation

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“…Although this status is crucial for the brain to remove senescent cells and extrinsic pathogenic substances, recent evidence has proven that chronic neuroinflammation is detrimental for the brain and may contribute to the etiology of various agingrelated neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) [2][3][4]. This notion was supported by previous findings that antiinflammatory therapies could halt the progression of AD and PD in animal models [5,6].…”

Section: Introductionmentioning

confidence: 79%

AVE0991, a nonpeptide analogue of Ang-(1-7), attenuates aging-related neuroinflammation

Jiang

Xue

Yang

et al. 2018

Aging

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During the aging process, chronic neuroinflammation induced by microglia is detrimental for the brain and contributes to the etiology of several aging-related neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. As a newly identified axis of renin-angiotensin system, ACE2/Ang-(1-7)/MAS1 axis plays a crucial role in modulating inflammatory responses under various pathological conditions. However, its relationship with aging-related neuroinflammation is less studied so far. In this study, by using SAMP8 mice, an animal model of accelerated aging, we revealed that the neuroinflammation in the aged brain might be attributed to a decreased level of Ang-(1-7). More importantly, we provided evidence that AVE0991, a nonpeptide analogue of Ang-(1-7), attenuated the aging-related neuroinflammation via suppression of microglial-mediated inflammatory response through a MAS1 receptor-dependent manner. Meanwhile, this protective effect might be ascribed to the M2 activation of microglia induced by AVE0991. Taken together, these findings reveal the association of Ang-(1-7) with the inflammatory response in the aged brain and uncover the potential of its nonpeptide analogue AVE0991 in attenuation of aging-related neuroinflammation.

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“…Studies show that BCG vaccination has a beneficial effect on neuroinflammation in an animal model of AD [150,151]. The pathology of AD includes accumulated amyloid plaques, tau tangles and persistent inflammation.…”

Section: Bcg and Alzheimer's Diseasementioning

confidence: 99%

Proposing BCG Vaccination for Mycobacterium avium ss. paratuberculosis (MAP) Associated Autoimmune Diseases

Dow

2020

Microorganisms

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Bacille Calmette–Guerin (BCG) vaccination is widely practiced around the world to protect against the mycobacterial infection tuberculosis. BCG is also effective against the pathogenic mycobacteria that cause leprosy and Buruli’s ulcer. BCG is part of the standard of care for bladder cancer where, when given as an intravesicular irrigant, BCG acts as an immunomodulating agent and lessens the risk of recurrence. Mycobacterium avium ss. paratuberculosis (MAP) causes a fatal enteritis of ruminant animals and is the putative cause of Crohn’s disease of humans. MAP has been associated with an increasingly long list of inflammatory/autoimmune diseases: Crohn's, sarcoidosis, Blau syndrome, Hashimoto’s thyroiditis, autoimmune diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis, lupus and Parkinson’s disease. Epidemiologic evidence points to BCG providing a “heterologous” protective effect on assorted autoimmune diseases; studies using BCG vaccination for T1D and MS have shown benefit in these diseases. This article proposes that the positive response to BCG in T1D and MS is due to a mitigating action of BCG upon MAP. Other autoimmune diseases, having a concomitant genetic risk for mycobacterial infection as well as cross-reacting antibodies against mycobacterial heat shock protein 65 (HSP65), could reasonably be considered to respond to BCG vaccination. The rare autoimmune disease, relapsing polychondritis, is one such disease and is offered as an example. Recent studies suggesting a protective role for BCG in Alzheimer’s disease are also explored. BCG-induced energy shift from oxidative phosphorylation to aerobic glycolysis provides the immunomodulating boost to the immune response and also mitigates mycobacterial infection—this cellular mechanism unifies the impact of BCG on the disparate diseases of this article.

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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

Cited by 53 publications

References 67 publications

Influenza vaccination in early Alzheimer’s disease rescues amyloidosis and ameliorates cognitive deficits in APP/PS1 mice by inhibiting regulatory T cells

Influenza vaccination in early Alzheimer’s disease rescues amyloidosis and ameliorates cognitive deficits in APP/PS1 mice by inhibiting regulatory T cells

AVE0991, a nonpeptide analogue of Ang-(1-7), attenuates aging-related neuroinflammation

Proposing BCG Vaccination for Mycobacterium avium ss. paratuberculosis (MAP) Associated Autoimmune Diseases

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