The Characterization of Peripheral and Neuro-inflammation Utilizing a 5xFAD Mouse Model

Abstract

Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder that is the cause of 60-70% of dementia cases in the United States (Holtzman, 2011). The hallmarks of AD include amyloid plaques, neurofibrillary tangles, and the loss of neuronal connections. This results in atrophy of brain tissues and inflammation. Current research studies use transgenic mouse models to understand the development and progression of AD over time. In this study, we used a 5xFAD mouse model which overexpress: (1) mutant human amyloid-β precursor protein AD mutations and (2) human presenilin 1 AD mutations. The objective of this study is to characterize peripheral and neuroinflammation utilizing this model. This characterization helps to determine the time frame in which therapeutics should be tested.Forty 5xFAD mice, 20 male and 20 female, were used in this experiment. Five mice per sex were euthanized at 5 weeks, 2 months, 5 months, and 7 months of age. The tissues collected from each mouse included the brain, meninges, blood, and spleen. The right brain, meninges, and isolated white blood cells underwent cell dissociation to be stained for flow cytometry. Results showed an increase of inflammatory responses between the two-month and five- months age groups. There was evidence of cross-talk between microglia and astrocytes via Interleukin-3 as well as an increased percent of activated glial cells. Sex differences were observed in the Neutrophil and Monocytes panel, as well as the ICAM+ Endothelial panel. Adhesion molecules were also increased over time, indicating activated endothelial responses. AD progression has influenced immune signaling pathways over time, with a significant increase occurring between two and five months of age in this 5xFAD mouse model.