Investigating the neuroimmunomodulatory effects of 40Hz light flicker treatment in 5xFAD model of Alzheimer’s Disease

AD is a chronic neurodegenerative condition affecting the aging population. Recently there has been global concern due to the rising prevalence of the disease and increasing financial burden of care. Despite the increasing prevalence of Alzheimer’s Disease (AD) there are currently no non-invasive treatments available for patients, with all available therapies only targeting the symptoms of disease and not the cause. Recently, a potential new form of treatment for AD has been gaining interest due to its non-invasive properties. Several studies have found that flickering a light at a 40Hz frequency was capable of reducing the disease pathology and improve memory retention in mouse models of AD via an unknown mechanism. We sought to unveil some of the mechanisms of this potential therapy. Using previously published methods we investigated the ability of 40Hz flickering light to reduce amyloid-β (Aβ) in the brains of 5xFAD mice- a transgenic mouse model of AD. We first used 9-month-old animals and treated for 1 hour a day for either 5 consecutive days or 15 days. In these 9-month-old animals we observed no significant changes in Aβ pathology (either plaque area or number) within the visual cortex (VC). We then changed the format of our treatment and reduced the ages of our animals to 4-5 months and revised our treatment equipment. At this reduced age we observed a significant reduction in total Aβ area alongside changes in gene expression in the VC for genes associated with the Aβ processing pathway, such as endogenous mouse APP and γ-secretase protein PSEN1. We then examined if the 40Hz light-flicker exhibited sex-dependent responses as previous studies have not examined sex-based differences. We observed that while some genes showed consistent changes between the sexes (PSEN1 & mAPP) some genes exhibited significant differences between male and female 5xFAD mice (BACE1 & Cst7), suggesting that the response was sex-dependent. Thus, 40Hz light flicker treatment reduced expression of Aβ in 4- 5-month-old 5xFAD mice as well as inducing significant changes in gene expression within the VC.AD is a chronic neurodegenerative condition affecting the aging population. Recently there has been global concern due to the rising prevalence of the disease and increasing financial burden of care. Despite the increasing prevalence of Alzheimer’s Disease (AD) there are currently no non-invasive treatments available for patients, with all available therapies only targeting the symptoms of disease and not the cause. Recently, a potential new form of treatment for AD has been gaining interest due to its non-invasive properties. Several studies have found that flickering a light at a 40Hz frequency was capable of reducing the disease pathology and improve memory retention in mouse models of AD via an unknown mechanism. We sought to unveil some of the mechanisms of this potential therapy. Using previously published methods we investigated the ability of 40Hz flickering light to reduce amyloid-β (Aβ) in the brains of 5xFAD mice- a transgenic mouse model of AD. We first used 9-month-old animals and treated for 1 hour a day for either 5 consecutive days or 15 days. In these 9-month-old animals we observed no significant changes in Aβ pathology (either plaque area or number) within the visual cortex (VC). We then changed the format of our treatment and reduced the ages of our animals to 4-5 months and revised our treatment equipment. At this reduced age we observed a significant reduction in total Aβ area alongside changes in gene expression in the VC for genes associated with the Aβ processing pathway, such as endogenous mouse APP and γ-secretase protein PSEN1. We then examined if the 40Hz light-flicker exhibited sex-dependent responses as previous studies have not examined sex-based differences. We observed that while some genes showed consistent changes between the sexes (PSEN1 & mAPP) some genes exhibited significant differences between male and female 5xFAD mice (BACE1 & Cst7), suggesting that the response was sex-dependent. Thus, 40Hz light flicker treatment reduced expression of Aβ in 4- 5-month-old 5xFAD mice as well as inducing significant changes in gene expression within the VC

Anti-CD52 antibody treatment in murine experimental autoimmune encephalomyelitis induces dynamic and differential modulation of innate immune cells in peripheral immune and central nervous systems

Anti-CD52 antibody (anti-CD52-Ab) leads to a rapid depletion of T and B cells, followed by reconstitution of immune cells with tolerogenic characteristics. However, very little is known about its effect on innate immune cells. In this study, experimental autoimmune encephalomyelitis mice were administered murine anti-CD52-Ab to investigate its effect on dendritic cells and monocytes/macrophages in the periphery lymphoid organs and the central nervous system (CNS). Our data show that blood and splenic innate immune cells exhibited significantly increased expression of MHC-II and costimulatory molecules, which was associated with increased capacity of activating antigen-specific T cells, at first day but not three weeks after five daily treatment with anti-CD52-Ab in comparison with controls. In contrast to the periphery, microglia and infiltrating macrophages in the CNS exhibited reduced expression levels of MHC-II and costimulatory molecules after antibody treatment at both time-points investigated when compared to controls. Furthermore, the transit response of peripheral innate immune cells to anti-CD52-Ab treatment was also observed in the lymphocyte-deficient SCID mice, suggesting the changes are not a direct consequence of the mass depletion of lymphocytes in the periphery. Our study demonstrates a dynamic and tissue-specific modulation of the innate immune cells in their phenotype and function following the antibody treatment. The findings of differential modulation of the microglia and infiltrating macrophages in the CNS in comparison with the innate immune cells in the peripheral organs support the CNS-specific beneficial effect of alemtuzumab treatment on inhibiting neuroinflammation in multiple sclerosis patients

Increased levels of IL-16 in the central nervous system during neuroinflammation are associated with infiltrating immune cells and resident glial cells

Interleukin (IL)-16, a CD4 + immune cell specific chemoattractant cytokine, has been shown to be involved in the development of multiple sclerosis, an inflammatory demyelinating disease of the central nervous system (CNS). While immune cells such as T cells and macrophages are reported to be the producers of IL-16, the cellular source of IL-16 in the CNS is less clear. This study investigates the correlation of IL-16 expression levels in the CNS with the severity of neuroinflammation and determines the phenotype of cells which produce IL-16 in the CNS of experimental autoimmune encephalomyelitis (EAE) mice. Our data show that IL-16 expression is significantly increased in the brain and spinal cord tissues of EAE mice compared to phosphate buffered saline (PBS) immunised controls. Dual immunofluorescence staining reveals that the significantly increased IL-16 + cells in the CNS lesions of EAE mice are likely to be the CD45 + infiltrating immune cells such as CD4 + or F4/80 + cells and the CNS resident CD11b + microglia and GFAP + astrocytes, but not NeuN+ neurons. Our data suggest cytokine IL-16 is closely involved in EAE pathology as evidenced by its increased expression in the glial and infiltrating immune cells, which impacts the recruitment and activation of CD4 + immune cells in the neuroinflammation