Tau in the gut, does it really matter?

Derkinderen, Pascal; Rolli–Derkinderen, Malvyne; Chapelet, Guillaume; Neunlist, Michel; Noble, Wendy

doi:10.1111/jnc.15320

Cited by 12 publications

(13 citation statements)

References 109 publications

(269 reference statements)

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“…Tau and its various isoforms have been extensively studied in neurons. Outside of the CNS, the health relevance of tau in the enteric nervous system is coming to light 40 . By contrast, the role of tau in non-neuronal cells remains poorly defined.…”

Section: Resultsmentioning

confidence: 99%

Multiple pathways promote microtubule stabilization in senescent intestinal epithelial cells

et al. 2022

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Intestinal epithelial cells are critical for gastrointestinal homeostasis. However, their function declines during aging. The aging-related loss of organ performance is largely driven by the increase in senescent cells. To date, the hallmarks and molecular mechanisms related to cellular senescence are not fully understood. Microtubules control epithelial functions, and we identified microtubule stabilization as a phenotypic marker of senescent intestinal epithelial cells. The senescence inducer determined the pathway to microtubule stabilization. Specifically, enhanced microtubule stability was associated with α-tubulin hyperacetylation or increased abundance of the microtubule-binding protein tau. We show further that overexpression of MAPT, which encodes tau, augmented microtubule stability in intestinal epithelial cells. Notably, pharmacological microtubule stabilization was sufficient to induce cellular senescence. Taken together, this study provides new insights into the molecular mechanisms that control epithelial cell homeostasis. Our results support the concept that microtubule stability serves as a critical cue to trigger intestinal epithelial cell senescence.

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Section: Resultsmentioning

confidence: 99%

Multiple pathways promote microtubule stabilization in senescent intestinal epithelial cells

et al. 2022

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“…These metabolites are essential for supporting cellular energetic processes, limiting redox stress, mitigating inflammation, and maintaining cell structure and signaling (Osellame et al, 2012;López-Armada et al, 2013;Smith and Aitchison, 2013;Di Cara, 2020). As mentioned previously, α-Synuclein inclusion bodies have been identified in the gut and enteric neurons of PD patients prior to the onset of disease, as well as in cases of inflammatory diseases that compromise the gut epithelial barrier (Hawkes et al, 2010;Challis et al, 2020;Derkinderen et al, 2021). α-Synuclein inclusions damage cellular mitochondrial functions, therefore, linking the diseases to metabolic and signaling dysfunction of mitochondria.…”

Section: Metabolic Alteration In the Gi As Markers Of Ndsmentioning

confidence: 88%

Towards early detection of neurodegenerative diseases: A gut feeling

Makdissi

Parsons

Cara

2023

Front. Cell Dev. Biol.

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The gastrointestinal tract communicates with the nervous system through a bidirectional network of signaling pathways called the gut-brain axis, which consists of multiple connections, including the enteric nervous system, the vagus nerve, the immune system, endocrine signals, the microbiota, and its metabolites. Alteration of communications in the gut-brain axis is emerging as an overlooked cause of neuroinflammation. Neuroinflammation is a common feature of the pathogenic mechanisms involved in various neurodegenerative diseases (NDs) that are incurable and debilitating conditions resulting in progressive degeneration and death of neurons, such as in Alzheimer and Parkinson diseases. NDs are a leading cause of global death and disability, and the incidences are expected to increase in the following decades if prevention strategies and successful treatment remain elusive. To date, the etiology of NDs is unclear due to the complexity of the mechanisms of diseases involving genetic and environmental factors, including diet and microbiota. Emerging evidence suggests that changes in diet, alteration of the microbiota, and deregulation of metabolism in the intestinal epithelium influence the inflammatory status of the neurons linked to disease insurgence and progression. This review will describe the leading players of the so-called diet-microbiota-gut-brain (DMGB) axis in the context of NDs. We will report recent findings from studies in model organisms such as rodents and fruit flies that support the role of diets, commensals, and intestinal epithelial functions as an overlooked primary regulator of brain health. We will finish discussing the pivotal role of metabolisms of cellular organelles such as mitochondria and peroxisomes in maintaining the DMGB axis and how alteration of the latter can be used as early disease makers and novel therapeutic targets.

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“…Thus, the reduced GI motility and increased bacterial load shown in the present study may apply to other types of degeneration. Although digestive disorders, including irritable bowel syndrome, have also been associated with AD and related dementias ( Liao et al, 2020 ), tau-mediated enteric nervous system changes remain poorly understood in tauopathies ( Chalazonitis and Rao, 2018 ; Derkinderen et al, 2021 ). As such, the present study provides a potential role of tau in enteric nervous system degeneration, perhaps contributing to gastrointestinal symptoms, including reduced gut motility.…”

Section: Discussionmentioning

confidence: 99%

Altered Gut Microbial Load and Immune Activation in a Drosophila Model of Human Tauopathy

et al. 2021

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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.

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Tau in the gut, does it really matter?

Cited by 12 publications

References 109 publications

Multiple pathways promote microtubule stabilization in senescent intestinal epithelial cells

Multiple pathways promote microtubule stabilization in senescent intestinal epithelial cells

Towards early detection of neurodegenerative diseases: A gut feeling

Altered Gut Microbial Load and Immune Activation in a Drosophila Model of Human Tauopathy

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