Impact of the Age of Cecal Material Transfer Donors on Alzheimer's Disease Pathology in 5xFAD Mice.

Alzheimer's disease is a progressive neurodegenerative disorder affecting around 30 million patients worldwide. The predominant sporadic variant remains enigmatic as the underlying cause has still not been identified. Since efficient therapeutic treatments are still lacking, the microbiome and its manipulation have been considered as a new, innovative approach. 5xFAD Alzheimer's disease model mice were subjected to one-time fecal material transfer after antibiotics-treatment using two types of inoculation: material derived from the caecum of age-matched (young) wild type mice or from middle aged, 1 year old (old) wild type mice. Mice were profiled after transfer for physiological parameters, microbiome, behavioral tasks, and amyloid deposition. A single time transfer of cecal material from the older donor group established an aged phenotype in the recipient animals as indicated by elevated cultivatable fecal Enterobacteriaceae and Lactobacillaceae representative bacteria, a decreased Firmicutes amount as assessed by qPCR, and by increased levels of serum LPS binding protein. While behavioral deficits were not accelerated, single brain regions (prefrontal cortex and dentate gyrus) showed higher plaque load after transfer of material from older animals. We could demonstrate that the age of the donor of cecal material might affect early pathological hallmarks of Alzheimer's disease. This could be relevant when considering new microbiome-based therapies for this devastating disorder.

Dietary Wheat Amylase Trypsin Inhibitors Impact Alzheimer's Disease Pathology in 5xFAD Model Mice.

Wheat amylase trypsin inhibitors (ATIs) represent a common dietary protein component of gluten-containing cereals (wheat, rye, and barley). They act as toll-like receptor 4 ligands, and are largely resistant to intestinal proteases, eliciting a mild inflammatory response within the intestine after oral ingestion. Importantly, nutritional ATIs exacerbated inflammatory bowel disease and features of fatty liver disease and the metabolic syndrome in mice. For Alzheimer's disease (AD), both inflammation and altered insulin resistance are major contributing factors, impacting onset as well as progression of this devastating brain disorder in patients. In this study, we evaluated the impact of dietary ATIs on a well-known rodent model of AD (5xFAD). We assessed metabolic, behavioral, inflammatory, and microbial changes in mice consuming different dietary regimes with and without ATIs, consumed ad libitum for eight weeks. We demonstrate that ATIs, with or without a gluten matrix, had an impact on the metabolism and gut microbiota of 5xFAD mice, aggravating pathological hallmarks of AD. If these findings can be translated to patients, an ATI-depleted diet might offer an alternative therapeutic option for AD and warrants clinical intervention studies.

Alzheimer's disease in the gut-Major changes in the gut of 5xFAD model mice with ApoA1 as potential key player.

Alzheimer's disease (AD) affects around 33 million people worldwide, which makes it the most prominent form of dementia. The main focus of AD research has been on the central nervous system (CNS) for long, but in recent years, the gut gained more attention. The intestinal tract is innervated by the enteric nervous system (ENS), built of numerous different types of neurons showing great similarity to neurons of the CNS. It already has been demonstrated that the amyloid precursor protein, which plays a major role in AD pathology, is also expressed in these cells. We analyzed gut tissue of AD model mice (5xFAD) and the respective wild-type littermates at different pathological stages: pre-pathological, early pathological and late pathological. Our results show significant difference in function of the intestine of 5xFAD mice as compared to wild-type mice. Using a pathway array detecting 84 AD-related gene products, we found ApoA1 expression significantly altered in colon tissue of 5xFAD mice. Furthermore, we unveil ApoA1's beneficial impact on cell viability and calcium homeostasis of cultured enteric neurons of 5xFAD animals. With this study, we demonstrate that the intestine is altered in AD-like pathology and that ApoA1 might be one key player within the gut.

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

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.

Identification of Patulin from Penicillium coprobium as a Toxin for Enteric Neurons.

The identification and characterization of fungal commensals of the human gut (the mycobiota) is ongoing, and the effects of their various secondary metabolites on the health and disease of the host is a matter of current research. While the neurons of the central nervous system might be affected indirectly by compounds from gut microorganisms, the largest peripheral neuronal network (the enteric nervous system) is located within the gut and is exposed directly to such metabolites. We analyzed 320 fungal extracts and their effect on the viability of a human neuronal cell line (SH-SY5Y), as well as their effects on the viability and functionality of the most effective compound on primary enteric neurons of murine origin. An extract from P. coprobium was identified to decrease viability with an EC50 of 0.23 ng/µL in SH-SY5Y cells and an EC50 of 1 ng/µL in enteric neurons. Further spectral analysis revealed that the effective compound was patulin, and that this polyketide lactone is not only capable of evoking ROS production in SH-SY5Y cells, but also diverse functional disabilities in primary enteric neurons such as altered calcium signaling. As patulin can be found as a common contaminant on fruit and vegetables and causes intestinal injury, deciphering its specific impact on enteric neurons might help in the elaboration of preventive strategies.