Erkert, Lena;
Gamez-Belmonte, Reyes;
Kabisch, Melanie;
Schödel, Lena;
Patankar, Jay V;
Gonzalez-Acera, Miguel;
Mahapatro, Mousumi;
... Becker, Christoph; + view all
(2024)
Alzheimer's disease-related presenilins are key to intestinal epithelial cell function and gut immune homoeostasis.
Gut
10.1136/gutjnl-2023-331622.
(In press).
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Abstract
OBJECTIVE: Mutations in presenilin genes are the major cause of Alzheimer's disease. However, little is known about their expression and function in the gut. In this study, we identify the presenilins Psen1 and Psen2 as key molecules that maintain intestinal homoeostasis. DESIGN: Human inflammatory bowel disease (IBD) and control samples were analysed for Psen1 expression. Newly generated intestinal epithelium-specific Psen1-deficient, Psen2-deficient and inducible Psen1/Psen2 double-deficient mice were used to dissect the functional role of presenilins in intestinal homoeostasis. RESULTS: Psen1 expression was regulated in experimental gut inflammation and in patients with IBD. Induced deletion of Psen1 and Psen2 in mice caused rapid weight loss and spontaneous development of intestinal inflammation. Mice exhibited epithelial barrier disruption with bacterial translocation and deregulation of key pathways for nutrient uptake. Wasting disease was independent of gut inflammation and dysbiosis, as depletion of microbiota rescued Psen-deficient animals from spontaneous colitis development but not from weight loss. On a molecular level, intestinal epithelial cells lacking Psen showed impaired Notch signalling and dysregulated epithelial differentiation. CONCLUSION: Overall, our study provides evidence that Psen1 and Psen2 are important guardians of intestinal homoeostasis and future targets for barrier-promoting therapeutic strategies in IBD.
| Type: | Article |
|---|---|
| Title: | Alzheimer's disease-related presenilins are key to intestinal epithelial cell function and gut immune homoeostasis |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1136/gutjnl-2023-331622 |
| Publisher version: | http://dx.doi.org/10.1136/gutjnl-2023-331622 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | EPITHELIAL BARRIER, GUT INFLAMMATION, IBD BASIC RESEARCH, INTESTINAL EPITHELIUM, MALNUTRITION |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10192367 |
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