The Synthetic Retinoid Acitretin Increases IL-6 in the Central Nervous System of Alzheimer Disease Model Mice and Human Patients.

Malena dos Santos Guilherme,Stefan Rose-John,Christoph Garbers,Nicolai M. Stoye,Andreas Fellgiebel,Kristina Endres

doi:10.3389/fnagi.2019.00182

Abstract

These days, the important role of retinoids in adult brain functionality and homeostasis is well accepted and has been proven by genomic as well as non-genomic mechanisms. In the healthy brain, numerous biological processes, e.g., cell proliferation, neurogenesis, dendritic spine formation as well as modulation of the immune system, have been attributed to retinoid signaling. This, together with the finding that retinoid metabolism is impaired in Alzheimer’s disease (AD), led to preclinical and early clinical testing of natural and synthetic retinoids as innovative pharmaceuticals with multifactorial properties. Acitretin, an aromatic retinoid, was found to exert an anti-amyloidogenic effect in mouse models for AD as well as in human patients by stimulating the alpha-secretase ADAM10. The lipophilic drug was already demonstrated to easily pass the blood brain barrier after i.p. administration and evoked increased nest building capability in the 5xFAD mouse model. Additionally, we analyzed the immune-modulatory capacity of acitretin via a multiplex array in the 5xFAD mouse model and evaluated some of our findings in human CSF derived from a pilot study using acitretin. Although several serum analytes did not display changes, Interleukin-6 (IL-6) was found to be significantly increased in both—mouse and human neural material. This demonstrates that acitretin exerts an immune stimulatory effect—besides the alpha-secretase induction—which could impact the alleviation of learning and memory disabilities observed in the mouse model.

Highlights

In a meta-analysis, significantly lower vitamin A plasma levels were found in Alzheimer’s disease (AD) patients (Lopes da Silva et al, 2014) and genetic linkages in regard to retinoic acid receptors as well as altered enzymatic function e.g., for retinaldehyde dehydrogenase (Connor and Sidell, 1997; Goodman and Pardee, 2003)
We treated 30-week-old 5xFAD mice with acitretin over 10 days: first, ADAM10 activity within brain homogenates of 5xFAD mice was decreased by ca. 40% as compared to wild type littermates (Figure 1B)
The IL-6 receptor may be shed by proteases such as ADAM10 (Garbers et al, 2011), form a soluble complex with IL-6, and stimulate cells that only express gp130 but not surface-bound IL-6R

Summary

Introduction

In a meta-analysis, significantly lower vitamin A plasma levels were found in Alzheimer’s disease (AD) patients (Lopes da Silva et al, 2014) and genetic linkages in regard to retinoic acid receptors as well as altered enzymatic function e.g., for retinaldehyde dehydrogenase (Connor and Sidell, 1997; Goodman and Pardee, 2003). Pre-clinical data support that retinoids might contribute to development and progression of AD: for example, vitamin A deficiency evoked in adult rodents cognitive impairment (Jiang et al, 2012; Hou et al, 2015) and a shift towards the amyloidogenic processing of the amyloid precursor protein (APP; Reinhardt et al, 2016). Rats fed on a MVAD diet with combinatory injection of Aβ showed cognitive impairment (Zeng et al, 2017b). This indicates that retinoic acid deficiency may lead to enhanced risk of developing AD and has given rise to the idea of using retinoids as therapeutics (Fahrenholz et al, 2010; Chakrabarti et al, 2016)

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