Bee venom phospholipase A2 ameliorates Alzheimer's disease pathology in Aβ vaccination treatment without inducing neuro-inflammation in a 3xTg-AD mouse model

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 (A beta) and tau proteins. Although vaccination against A beta peptide results in a dramatic reduction in A beta pathology in experimental mouse models, the initial clinical trial for an active A beta vaccine was halted early due to the development of acute meningoencephalitis in 6% of the immunized patients, which likely involved a T-cell mediated proinflammatory 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 A beta vaccination. Inflammatory aggregates of CD3(+) T lymphocytes and macrophages were found in the brains and spinal cords of mice treated with A beta. However, administration of bvPLA2 dramatically eliminated central nervous system inflammation following A beta immunization. In AD model mice (3xTg-AD mice), bvPLA2 administration significantly ameliorated cognitive deficits and reduced A beta burdens in the brains of A beta-vaccinated 3xTg-AD mice. Additionally, we examined brain glucose metabolism using positron emission tomography with F-18-2 fluoro-2-deoxy-D-glucose. Cerebral glucose uptake was considerably higher in the brains of A beta-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 A beta vaccination therapy without an adverse inflammatory response.