Abstract
Alzheimer’s disease (AD) is the most common form of dementia and is characterized by an imbalance between the production and clearance of amyloid-beta (Aβ) and tau proteins. Although vaccination against Aβ peptide results in a dramatic reduction in Aβ pathology in experimental mouse models, the initial clinical trial for an active Aβ vaccine was halted early due to the development of acute meningoencephalitis in 6% of the immunized patients, which likely involved a T-cell mediated pro-inflammatory response. In this study, we aimed to determine whether bee venom phospholipase A2 (bvPLA2) treatment would induce Tregs and ameliorate AD pathology without unwanted T cell-mediated inflammation. First, we investigated the effects of bvPLA2 on the inflammatory infiltration caused by Aβ vaccination. Inflammatory aggregates of CD3+ T lymphocytes and macrophages were found in the brains and spinal cords of mice treated with Aβ. However, administration of bvPLA2 dramatically eliminated central nervous system inflammation following Aβ immunization. In AD model mice (3xTg-AD mice), bvPLA2 administration significantly ameliorated cognitive deficits and reduced Aβ burdens in the brains of Aβ-vaccinated 3xTg-AD mice. Additionally, we examined brain glucose metabolism using positron emission tomography with 18F-2 fluoro-2-deoxy-d-glucose. Cerebral glucose uptake was considerably higher in the brains of Aβ-vaccinated 3xTg-AD mice that received bvPLA2 than those that did not. The present study suggests that the modulation of Treg populations via bvPLA2 treatment may be a new therapeutic approach to attenuate the progression of AD in conjunction with Aβ vaccination therapy without an adverse inflammatory response.
Highlights
A2 treatment would induce Tregs and ameliorate Alzheimer’s disease (AD) pathology without unwanted T cellmediated inflammation
Our findings demonstrate that bee venom phospholipase A2 (bvPLA2)-mediated expansion of Tregs together with co-immunization of Aβ42 vaccine may have distinct effects on immunosuppressive responses, facilitating a balance in homeostasis in the context of neurodegenerative diseases, including AD. bvPLA2-mediated induction of Tregs improved cognitive function, reduced Aβ deposition and the production of inflammatory cytokines, and increased glucose uptake in Aβ-vaccinated 3xTg-AD mice
The data reported here support the idea that the use of bvPLA2 in Aβ vaccination treatment may lead to a reduction in aberrant autoimmune reactions against Aβ that provoke central nervous system (CNS) inflammation
Summary
A2 (bvPLA2) treatment would induce Tregs and ameliorate AD pathology without unwanted T cellmediated inflammation. In AD model mice (3xTg-AD mice), bvPLA2 administration significantly ameliorated cognitive deficits and reduced Aβ burdens in the brains of Aβ-vaccinated 3xTg-AD mice. The present study suggests that the modulation of Treg populations via bvPLA2 treatment may be a new therapeutic approach to attenuate the progression of AD in conjunction with Aβ vaccination therapy without an adverse inflammatory response. Active immunization following vaccination against Aβ1-42 peptide was reported to have a therapeutic effect in a murine model of AD6,7. In view of these encouraging results, a clinical Aβ vaccination trial (AN1792) was initiated, and modest beneficial effects were observed in a cohort of Aβ1-42-immunized AD patients. To avoid a T cell-mediated immune response after active vaccination, current alternative vaccination strategies are focused on generating epitope-specific Aβ peptides
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