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

Abstract

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.

Blood-Based Biomarkers for Alzheimer’s Disease Diagnosis and Progression: An Overview

“…For example, increased levels of circulating LPS, the main component of the outer membrane in Gram-negative bacteria, have been identified in MCI and AD patients [ 383 ]. Indeed, LPS can induce the activation of pro-inflammatory pathways, promoting BBB disruption and neuroinflammation [ 384 , 385 ]. Furthermore, short-chain fatty acids (SCFAs), usually beneficial for their anti-inflammatory and antioxidant properties in the intestinal lumen, can be released in the blood upon dysbiosis, reach the cerebral circulation, and cause potentially harmful effects on brain function [ 383 , 386 , 387 ].…”

5xFAD mice do not have myenteric amyloidosis, dysregulation of neuromuscular transmission or gastrointestinal dysmotility

“…In addition, neuronal loss in the CNS occurs at 3 months, and cognitive impairment is observed at 5 months of age 25,26 . Literature has reported that 5xFAD mice also present minor GI dysmotility, 22,27 changes in enteric neuronal structure, 27 altered colonic gene expressions and calcium homeostasis, increased enteric neuronal viability, 22 and GI dysbiosis 28 . However, there is no study directly supporting that Aβ accumulation occurs in enteric ganglia in the myenteric plexus of 5xFAD mice and if Aβ accumulation disrupts myenteric neuromuscular transmission causing GI dysmotility.…”

Resilience and the Gut Microbiome: Insights from Chronically Socially Stressed Wild-Type Mice

“…This treatment was based on [1]. In our previous experiments conducted in Alzheimer's disease model mice [23], we observed an effective reduction in the gut microbiome by a similar antibiotics cocktail. Probiotics-treated animals received 10 9 CFU/mL (OptiBac for those on antibiotics, OptiBac Probiotics HQ Wren Laboratories Ltd., Hampshire, UK, contains L. acidophilus and L. rhamnosus), which resulted in elevated amounts of Lactobacillaceae in another mouse strain [23] and is in accordance with other published treatment approaches in rodents (for example, [24,25]).…”

“…For males, collection of feces was conducted with euthanization (22 weeks of age). Fecal samples were analyzed at the MVZ Institut fuer Mikrooekologie GmbH (Herborn, Germany) as described before [23]. Standard curves were produced using the appropriate reference organism to quantify qPCR values into the number of bacteria per gram (wet weight).…”