Revisiting rodent models: Octodon degus as Alzheimer's disease model?

Johannes Steffen,Christina Schwitlick,Andreas Müller-Schiffmann,Carsten Korth,Markus Krohn,Katharina Braun,Kristin Paarmann,Rita Marreiros,Thomas Brüning,Jens Pahnke

doi:10.1186/s40478-016-0363-y

Abstract

Alzheimer’s disease primarily occurs as sporadic disease and is accompanied with vast socio-economic problems. The mandatory basic research relies on robust and reliable disease models to overcome increasing incidence and emerging social challenges. Rodent models are most efficient, versatile, and predominantly used in research. However, only highly artificial and mostly genetically modified models are available. As these ‘engineered’ models reproduce only isolated features, researchers demand more suitable models of sporadic neurodegenerative diseases. One very promising animal model was the South American rodent Octodon degus, which was repeatedly described as natural ‘sporadic Alzheimer’s disease model’ with ‘Alzheimer’s disease-like neuropathology’. To unveil advantages over the ‘artificial’ mouse models, we re-evaluated the age-dependent, neurohistological changes in young and aged Octodon degus (1 to 5-years-old) bred in a wild-type colony in Germany. In our hands, extensive neuropathological analyses of young and aged animals revealed normal age-related cortical changes without obvious signs for extensive degeneration as seen in patients with dementia. Neither significant neuronal loss nor enhanced microglial activation were observed in aged animals. Silver impregnation methods, conventional, and immunohistological stains as well as biochemical fractionations revealed neither amyloid accumulation nor tangle formation. Phosphoepitope-specific antibodies against tau species displayed similar intraneuronal reactivity in both, young and aged Octodon degus.In contrast to previous results, our study suggests that Octodon degus born and bred in captivity do not inevitably develop cortical amyloidosis, tangle formation or neuronal loss as seen in Alzheimer’s disease patients or transgenic disease models.

Highlights

Senile plaques, a hallmark of Alzheimer’s disease (AD), were long suggested to initiate the destructive cascade to progressive neuronal dysfunction and death
Microglia-specific stains of ionized calcium-binding adapter molecule 1 (IBA1), which can unravel early signs of pathology shown by localised microglia accumulation, displayed homogenously distributed populations of resting microglia in young and aged animals (Fig. 2e, f)
Octodon degus was re-evaluated in the context of existing rodent AD models and human AD pathology

Summary

Introduction

A hallmark of Alzheimer’s disease (AD), were long suggested to initiate the destructive cascade to progressive neuronal dysfunction and death. Soluble oligomers of β-amyloid (Aβ) are deemed the primary toxic species [1]. These oligomers disrupt a variety of receptors [2], increase membrane permeability [2] and are suspected to induce hyperphosphorylation and aggregation of tau [3]. A small proportion of AD cases involve genetic variations which entail alterations in amount, ratio or amino acid sequence of Aβ [9]. These rare inherited forms are the fundament of both, disease models and our current understanding of AD. To successfully combat the sporadic form of AD, models that develop the disease on a more ‘natural’ basis would certainly help to understand the underlying

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