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

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.

Impact of Gut Microbiome Manipulation in 5xFAD Mice on Alzheimer’s Disease-Like Pathology

“…XBP-1 splicing and thereby activation of the transcription factor probability was considered as it has previously been identified as an alpha-secretase gene expression enhancer [ 36 ]. Stimulation of alpha-secretase ADAM10 expression and by this elevation of enzymatic activity could have explained the reduced Aβ deposition and in consequence improved the cognitive function of the mice (e.g., as shown by the pharmacological inducer acitretin, [ 27 ]). However, neither the amount of XBP-1 derived from the unspliced mRNA nor the protein derived from the spliced mRNA was affected in the brains of antibiotics-treated 5xFAD mice.…”

“…The nest building test was performed as described previously [ 27 ]. In brief, animals were habituated to a special nesting material and received 10 g of nesting material for overnight nest building.…”

Shotgun lipidomics of liver and brain tissue of Alzheimer’s disease model mice treated with acitretin

“…This aromatic derivative has also been identified as a potential drug for treating Alzheimer’s disease (AD) in a re-purposing screening attempt 5 . It showed in vitro but also in vivo favorable effects on hallmarks of the disease: for example, it enhanced α-secretase expression and activity in human neuronal cells and in mouse models of the disease 6 , 7 . This enzyme has been demonstrated to be protective against neurotoxic pathways of the disease such as the synthesis of amyloid-β (Aβ) peptides and e.g.…”

Pharmacologic Inhibition of ADAM10 Attenuates Brain Tissue Loss, Axonal Injury and Pro-inflammatory Gene Expression Following Traumatic Brain Injury in Mice

“…To the best of our knowledge, there are no published data on a possible connection between LCN2 and ADAM10 but several studies support a regulatory role of ADAM10 in TNFα and IL-6 mediated actions. ADAM10 cleaves and thereby mediates the release of TNFα ( Arduise et al, 2008 ) and has also been linked to the regulation of neural IL-6 levels after activation by aromatic retinoid acetritin ( Dos Santos Guilherme et al, 2019 ). It has been further reported that TNFα-induced apoptosis can be regulated via an ADAM10-NF-κB feedback loop in a B cell lymphoma cell line ( Yang et al, 2019 ).…”