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

Abstract

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.

Malaria Related Neurocognitive Deficits and Behavioral Alterations

“…In the last few years, evidence has accumulated pointing to the ability of immune stimuli to modulate neurogenesis, synaptic plasticity, in addition to cognitive and behavioral function ( Xia et al., 2014 ; Li et al., 2015 ; Li et al., 2016 ; Yang et al., 2016 ; Qi et al., 2017 ; Yang et al., 2020 ; De Sousa et al., 2021 ). These findings support the concept of consistent communication and interrelationship between the nervous and immune systems, as plastic and cognitive systems ( Jerne and Cocteau, 1984 ; Pert et al., 1985 ; Cohen, 1992 ; Sawada et al., 1993 ; Josefsson et al., 1996 ; Amenta et al., 2002 ; McKenna et al., 2002 ; Daniel-Ribeiro and Martins, 2017 ) and the use of immunomodulation as a promising approach in the treatment of neurocognitive and behavioral sequelae of infectious diseases.…”

Is SARS-CoV-2 vaccination safe and effective for elderly individuals with neurodegenerative diseases?

“…These data indicate that AD patients can preserve their immune response to the vaccines, but the effectiveness of the vaccines may gradually decrease with age. Animal studies have shown that the systemic immunity induced by influenza vaccination can inhibit the systemic immune suppression caused by Treg cells and restore the ability of microglia to clear Aβ, thus improving cognitive dysfunction [ 55 ]. No serious adverse reactions from the inactivated influenza vaccine were observed in patients with neurodegenerative diseases compared with a control group [ 54 ].…”

Perspective: Treatment for Disease Modification in Chronic Neurodegeneration

“…As a next step, a shift from active to passive immunization is now under way in AD models [ 75 ]. It is regarded as more safe, to be better controlled and may also be efficacious [ 79 , 80 , 81 , 82 ]. However, will vaccination against aggregated β-amyloid plaques be beneficial for other pathological processes associated with AD, like the tau-protein pathology?…”