Cortical iron regulation and inflammatory response in Alzheimer's disease and APPSWE/PS1ΔE9 mice: a histological perspective.

Mark D Meadowcroft,Qing X Yang,James R Connor

doi:10.3389/fnins.2015.00255

Abstract

Disruption of iron homeostasis and increased glial response are known to occur in brains afflicted by Alzheimer's disease (AD). While the APP/PS1 transgenic mouse model recapitulates the hallmark amyloid-beta plaque pathology of AD, it does so in a different neuronal mileu than humans. Understanding the iron characteristics and glial response of the APP/PS1 model is important when testing new treatment procedures and translating these results. Brain tissue from AD patients, APP/PS1 mice, and controls were stained for iron, H- and L-ferritin, microglia, astrocytes, Aβ40∕42, and degenerating neurons. The histological data demonstrate differences in ferritin, iron distribution, gliosis, and Aβ plaque composition between APP/PS1 and AD tissue. Specifically, an association between focal iron deposition and Aβ plaques is found ubiquitously throughout the AD tissue and is not observed in the APP/PS1 mouse model. Ferritin, microglia, and astrocyte staining show differential response patterns to amyloid plaques in AD and the APP/PS1 tissue. Aβ 40 and 42 antibody and thioflavin staining demonstrate morphological differences in plaque composition. The histological data support the hypothesis that iron distribution, iron management, and glial response histologically differ between the APP/PS1 and AD brain. Acknowledging the caveat that there are distinct plaque, iron, and glial contrasts between the AD brain and the APP/PS1 mouse is crucial when utilizing this model.

Highlights

The extracellular formation of amyloid-beta (Aβ) protein plaques is a major defining neuropathological characteristic of Alzheimer’s disease (AD)
Our results provide new information on iron association, inflammatory response, Aβ plaque morphology, and related neurodegeneration in AD and amyloid precursor protein (APP)/presenilin 1 (PS1) brain tissue samples which allow us to examine the hypothesis that iron regulation and the associated inflammatory response contrasts between the APP/PS1 and AD brain in these aspects
While regulation of iron has been shown to be associated with the neurodegenerative processes in AD (Gerlach et al, 1994), the causative relationship between disease pathology and iron regulation has not been resolved

Summary

Introduction

The extracellular formation of amyloid-beta (Aβ) protein plaques is a major defining neuropathological characteristic of Alzheimer’s disease (AD). Transgenic mouse models have been developed to mimic the formation of Aβ plaques within neural tissue (Borchelt et al, 1996, 1997) and are especially important for understanding disease etiology and testing new therapeutic procedures (Siman et al, 2000; Jankowsky et al, 2001; Dewachter et al, 2002; Richards et al, 2003; Casas et al, 2004) These specific transgenic mice harbor chimeric mouse/human familial AD genes for amyloid precursor protein (APP) and a mutant human presenilin 1 (PS1) under control of the AD and APP/PS1 histology mouse prion promoter. The data strongly suggest that there is a disruption in brain iron homeostasis associated with AD and that the misregulation of iron plays a central role in disease pathology

Methods

Results

Conclusion