Innate immune alterations are elicited in microglial cells before plaque deposition in the Alzheimer\u2019s disease mouse model 5xFAD

Antonio Boza-Serrano,Agnes Paulus,Yiyi Yang,Tomas Deierborg

doi:10.1038/s41598-018-19699-y

Abstract

Alzheimer’s disease (AD) is the most common form of dementia characterized by the formation of amyloid plaques (Aβ). Over the last decade, the important role of the innate immune system for the disease development has been established. Chronic activation of microglial cells creates a proinflammatory environment, which is believed to be central for the development of the disease as well as its progression. We used the AD mouse model 5xFAD to investigate if inflammatory alterations are present in microglial cells before plaque deposition. We applied mass spectrometry and bioinformation analysis to elucidate early microglial alterations. Interestingly, we found the cytokines IL1β and IL10 to be elevated in the 5xFAD brain after the formation of Aβ plaque at 10 weeks only. Using mass spectrometry analysis of microglial cells with bioinformation analysis, we found JAK/STAT, p38 MAPK and Interleukin pathways affected in microglial cells before plaque deposition at 6 weeks. At 10 weeks, GO analysis showed affected pathways related to interferon-gamma regulation and MAPK pathways. Our study points toward early inflammatory changes in microglial cells even before the accumulation of Aβ.

Highlights

Alzheimer’s disease (AD) is a neurodegenerative disease affecting more than 24 million people worldwide and future projections predicts almost 50 millions people affected by 20301
We studied inflammatory alterations related to microglial cells and we found a clear inflammatory activation in microglial cells isolated before Aβ plaque deposition with altered cytokine levels in the 5xFAD brain and upregulation of proteins related to JAK-STAT, MAPK and Interleukins pathways along with a significant increase in the soluble Aβ levels
We describe microglial changes in the very early phase of AD pathogenesis before plaque deposition in the brain of 5xFAD mice

Summary

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disease affecting more than 24 million people worldwide and future projections predicts almost 50 millions people affected by 20301. Future therapeutic approaches are aiming for early treatment, even presymptomatic, to effectively fight the disease progression For this reason, it is important to study how the disease progresses before the appearance of the first plaques. It is plausible that early microglial activation can be one of the first pathological processes involved in the initiation of the disease due to the capacity of lower molecular Aβ species to activate microglial cells in vitro[9] These Aβ molecules can be found in the extracellular environment, before the typical plaque deposition and by that activate/ alter microglial function. Our study reveals a number of different pathways related with the innate immune system response, potentially involved in the progression of the disease, even before the first plaque deposition.

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