Alzheimer’s disease (AD) is a progressive neurodegenerative disease mostly associated with cognitive decline. Aging represents a major, if not, the biggest risk factor of developing AD. Converging evidence from both genetic at-risk cohorts and clinically normal older individuals suggests that the pathophysiological process of AD begins years, if not decades, before the diagnosis of clinical dementia. Besides alterations affecting the brain, increasing evidence suggest the presence of gastrointestinal (GI) comorbidities such as constipation, and diarrhea in AD, whose underlying phaysiopahtological process remain unknown. The enteric nervous system (ENS) is the intrinsic nervous system of the GI tract with neurons organized in microcircuits allowing for modulation of GI functions by various neuromediators and neurotrophic factors. We have recently shown that the neurotrophic factor EphB2, a key molecule regulating the connectivity/plasticity of neurons in the central nervous system, also regulates enteric neuronal connectivity and activity through control of synaptic-associated proteins. Furthermore, alterations in the ENS and GI dysfunctions, ranging from loss of neurons, changes in neuromediators expression, intestinal dysmotility have been reported in animal models of AD. Furthermore, deposits of Amyloid-β (Aβ), Aβ1-40 and Aβ1-42 which are peptidic forms of Aβ (40 or 42 residues in length) that have been primarily involved in brain Aβ pathology in AD, and its precursor protein βAPP have been observed in the gut of AD patients.
Interestingly, many studies have highlighted the important role of nutrition in the regulation of cognitive and digestive functions. Interestingly, the gut microbiota and its metabolites can also impact these functions. Among metabolites of interest are short chain fatty acids (SCFAs), produced by the anaerobic microbial fermentation of non-digestible dietary fibers. They are naturally synthesized by the microbiota, mainly in the colon and their central role not only in neuronal metabolism but also in the modulation of genes involved in neuronal connectivity (such as the neurotrophic factor BDNF) has recently been highlighted. In addition, other studies have shown the beneficial effects of vitamins such as folate (Vitamin B9) in physiological and pathophysiological brain aging. Nevertheless, the ability of SCFAs or vitamins to prevent gastrointestinal dysfunction and/or cognitive decline in AD pathology and their mode of action are largely unknow.
Thus, our research focuses on the gut-brain axis with a particular interest on microbiota dysbiosis as potential modulator of enteric Aβ pathology in AD and alterations of enteric neuronal connectivity and its functional consequences.
Some questions addressed in ongoing studies :
1. Does Aβ affect enteric neuronal connectivity ?
2. Does Aβ induce gastrointestinal dysfunctions ?
3. Can microbiota dysbiosis promote enteric Aβ pathology ?
4. Through which mechanisms does microbiota affect enteric functions in AD ?
5. Which probiotics or bacterial metabolites can ameliorate or prevent gut remodeling in AD ?
Thus, our research focuses on the gut-brain axis with a particular interest on the gut as a potential early site of Aβ pathology and alterations of enteric neuronal connectivity and functional consequences with an emphasis on AD pathology.
Researchers / Clinicians
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Bodin R, Paillé V, Oullier T, Durand T, Aubert P, Le Berre-Scoul C, Hulin P, Neunlist N, Cissé M. The ephrin receptor EphB2 regulates the connectivity and activity of enteric neurons. J Biol Chem. 2021 Oct 11;297(5):101300. PMID: 34648765. Link
The transcription factor XBP1 in memory and cognition: Implications in Alzheimer disease.Cissé M, Duplan E, Checler F. Mol Med. 2017 Feb;22:905-917. PMID: 28079229. Link
The transcription factor XBP1s restores hippocampal synaptic plasticity and memory by control of the Kalirin-7 pathway in Alzheimer model. Cissé M, Duplan E, Lorivel T, Dunys J, Bauer C, Meckler X, Gerakis Y, Lauritzen I, Checler F. Mol Psychiatry. 2017 Nov;22(11):1562-1575. PMID: 27646263 Link
Ablation of cellular prion protein does not ameliorate abnormal neural network activity or cognitive dysfunction in the J20 line of human amyloid precursor protein transgenic mice. Cissé M, Sanchez PE, Kim DH, Ho K, Yu GQ, Mucke L. J Neurosci. 2011 Jul 20;31(29):10427-31. PMID: 21775587. Link
Reversing EphB2 depletion rescues cognitive functions in Alzheimer model. Cissé M, Halabisky B, Harris J, Devidze N, Dubal DB, Sun B, Orr A, Lotz G, Kim DH, Hamto P, Ho K, Yu GQ, Mucke L. Nature. 2011 Jan 6;469(7328):47-52. doi: 10.1038/nature09635. Epub 2010 Nov 28. PMID: 21113149. Link
Alzheimer's disease: A prion protein connection. Cisse M, Mucke L. Nature. 2009 Feb 26;457(7233):1090-1. doi: 10.1038/4571090a. PMID: 19242462. Link
Neprilysin overexpression inhibits plaque formation but fails to reduce pathogenic Abeta oligomers and associated cognitive deficits in human amyloid precursor protein transgenic mice. Meilandt WJ, Cisse M, Ho K, Wu T, Esposito LA, Scearce-Levie K, Cheng IH, Yu GQ, Mucke L. J Neurosci. 2009 Feb 18;29(7):1977-86. doi: 10.1523/JNEUROSCI.2984-08.2009. PMID: 19228952. Link