Osteoarthritis accelerates and exacerbates Alzheimer's disease pathology in mice

Stephanos Kyrkanides,Jen-Nie H Miller,M Kerry O'Banion,Mallory E Olschowka,Renee Johnson,John A Olschowka,Meixiang Yang,Sabine M Brouxhon,Ross H Tallents

doi:10.1186/1742-2094-8-112

Abstract

BackgroundThe purpose of this study was to investigate whether localized peripheral inflammation, such as osteoarthritis, contributes to neuroinflammation and neurodegenerative disease in vivo.MethodsWe employed the inducible Col1-IL1βXAT mouse model of osteoarthritis, in which induction of osteoarthritis in the knees and temporomandibular joints resulted in astrocyte and microglial activation in the brain, accompanied by upregulation of inflammation-related gene expression. The biological significance of the link between peripheral and brain inflammation was explored in the APP/PS1 mouse model of Alzheimer's disease (AD) whereby osteoarthritis resulted in neuroinflammation as well as exacerbation and acceleration of AD pathology.ResultsInduction of osteoarthritis exacerbated and accelerated the development of neuroinflammation, as assessed by glial cell activation and quantification of inflammation-related mRNAs, as well as Aβ pathology, assessed by the number and size of amyloid plaques, in the APP/PS1; Col1-IL1βXAT compound transgenic mouse.ConclusionThis work supports a model by which peripheral inflammation triggers the development of neuroinflammation and subsequently the induction of AD pathology. Better understanding of the link between peripheral localized inflammation, whether in the form of osteoarthritis, atherosclerosis or other conditions, and brain inflammation, may prove critical to our understanding of the pathophysiology of disorders such as Alzheimer's, Parkinson's and other neurodegenerative diseases.

Highlights

The purpose of this study was to investigate whether localized peripheral inflammation, such as osteoarthritis, contributes to neuroinflammation and neurodegenerative disease in vivo
We report that localized induction of osteoarthritis in the young adult APP/PS1 mouse model of Alzheimer’s disease (AD) leads to glial activation as well as acceleration and exacerbation of AD plaque pathology
We examined whether endogenous, murine cytokines were elevated in the blood stream of these mice: Mice injected with FIV(Cre) demonstrated a 3.8 fold increase (p < 0.016, F = 7.28) relative to controls in Overall, (E) APP/PS1 mice with arthritis displayed a significantly greater number of Ab plaques at every time point examined, as well as developed Ab plaque deposits the 4 month time point when no plaques were observed in APP/PS1 mice without arthritis. (F) There was a modest increase in the number of small Ab plaque deposits (< 100 μm) after osteoarthritis throughout the brain of Col1-IL1bXAT;APP/PS1 mice with osteoarthritis

Summary

Introduction

The purpose of this study was to investigate whether localized peripheral inflammation, such as osteoarthritis, contributes to neuroinflammation and neurodegenerative disease in vivo. LPS administration to AD mouse models has given mixed results, with some investigators reporting exacerbation [12,13,14] and others improvement of pathology due to an inflammationinduced phagocytic activity [15,16,17]. To this end, overexpression of inflammatory cytokines in the brain of AD mouse models resulted in alleviation of AD pathology [18], including our own where sustained expression of interleukin-1b (IL-1b) in mouse hippocampus promoted plaque clearance in the APP/PS1 double transgenic mouse model [19]

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