Abstract
Tau is a microtubule-associated protein that stabilizes the neuronal cytoskeleton. In the family of neurodegenerative diseases known as tauopathies, including Alzheimer’s disease (AD), frontotemporal dementia (FTD), and chronic traumatic encephalopathy (CTE), abnormal tau aggregation destabilizes microtubule structure, contributing to a cascade of cellular processes leading to neuronal cell death. The gut microbiome has increasingly become a target of neurodegenerative disease research since gut microbiome imbalances have been linked to protein aggregation and inflammation through a bidirectional axis linking the gut and brain. Accordingly, the present study examined tau-mediated changes to gut microbiome composition and immune activation in a Drosophila melanogaster model of human mutant tauopathy. Fecal deposit quantification and gastric emptying time courses suggested an abnormal food distribution and reduced gut motility in tau transgenic flies compared to controls. Tau transgenic flies also showed an increase in gut bacteria colony forming units (CFUs) from diluted fly homogenate, indicating an increased bacterial load. Finally, we showed that tau transgenic flies have a trend towards elevated systemic levels of antimicrobial peptides targeting gram-negative bacteria using qPCR, suggesting an enhanced innate immune response to bacterial insult. These data demonstrate qualifiable and quantifiable gut microbial and innate immune responses to tauopathy. Furthermore, these results provide a framework for future studies targeting the gut microbiome as a modifier of neurodegenerative disease.
Highlights
Accumulation of the microtubule-associated protein tau is the hallmark pathology of the family of neurodegenerative diseases known as tauopathies, which includes Alzheimer’s disease (AD), frontotemporal dementia (FTD), and chronic traumatic encephalopathy (CTE)
Using the transgenic expression of mutant human FTDP-17– associated tau, tauR406W, in Drosophila, we showed a reduced gut motility and subsequently increased gut bacterial load in aged tau transgenic flies compared to controls
We showed no significant changes in motility in the SCA3 Drosophila model of spinocerebellar ataxia type 3 (SCA3; Machado-Joseph disease) (Warrick et al, 1998)
Summary
Accumulation of the microtubule-associated protein tau is the hallmark pathology of the family of neurodegenerative diseases known as tauopathies, which includes Alzheimer’s disease (AD), frontotemporal dementia (FTD), and chronic traumatic encephalopathy (CTE). The human gut microbiome, colonized at birth, encompasses the collective genome of approximately one-hundred trillion microorganisms residing in the gastrointestinal (GI) tract (Ghaisas et al, 2016). These gut microbes contribute to the preservation of human health through various mechanisms including the extraction and absorption of nutrients from food, protection against pathogen overgrowth, biosynthesis of vitamins, amino acids, and peptides, interactions with the intestinal epithelium, and modulation of the immune system (Hooper et al, 2012; Zhao et al, 2015). Of particular interest is the implication of microbiome dysbiosis on neurological disorders and neurodegenerative diseases, as mediated by the gut-brain axis
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