Chronic administration of prebiotics and probiotics ameliorates pathophysiological hallmarks of Alzheimer’s disease in a APP/PS1 transgenic mouse model

Introduction: The gut microbiota (MB), although one of the main producers of A beta in the body, in physiological conditions contributes to the maintainance of a healthy brain. Dysbiosis, the dysbalance between Gram-negative and Gram-positive bacteria in the MB increases A beta production, contributing to the accumulation of A beta plaques in the brain, the main histopathological hallmark of Alzheimer's disease (AD). Administration of prebiotics and probiotics, maintaining or recovering gut-MB composition, could represent a nutraceutical strategy to prevent or reduce AD sympthomathology. Aim of this research was to evaluate whether treatment with pre- and probiotics could modify the histopathological signs of neurodegeneration in hippocampal CA1 and CA3 areas of a transgenic mouse model of AD (APP/PS1 mice). The hippocampus is one of the brain regions involved in AD.Methods: Tg mice and Wt littermates (Wt-T and Tg-T) were fed daily for 6 months from 2 months of age with a diet supplemented with prebiotics (a multi-extract of fibers and plant complexes, containing inulin/fruit-oligosaccharides) and probiotics (a 50%-50% mixture of Lactobacillus rhamnosus and Lactobacillus paracasei). Controls were Wt and Tg mice fed with a standard diet. Brain sections were immunostained for A beta plaques, neurons, astrocytes, microglia, and inflammatory proteins that were evaluated qualitatively and quantitatively by immunofluorescence, confocal microscopy and digital imaging with ImageJ software.Results: Quantitative analyses demonstrated that: 1) The treatment with pre- and probiotics significantly decreased A beta plaques in CA3, while in CA1 the reduction was not significant; 2) Neuronal damage in CA1 Stratum Pyramidalis was significantly prevented in Tg-T mice; no damage was found in CA3; 3) In both CA1 and CA3 the treatment significantly increased astrocytes density, and GFAP and IBA1 expression, especially around plaques; 4) Microglia reacted differently in CA1 and CA3: in CA3 of Tg-T mice there was a significant increase of CD68+ phagocytic microglia (ball-and-chain phenomic) and of CX3CR1 compared with CA1.Discussion: The higher microglia reactivity could be responsible for their more efficient scavenging activity towards A beta plaques in CA3 in comparison to CA1. Treatment with pre- and probiotics, modifying many of the physiopathological hallmarks of AD, could be considered an effective nutraceutical strategy against AD symptomatology.