Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily associated with cognitive decline. Aging is a major, if not the most important, risk factor for developing AD. Converging evidence from both genetically at-risk cohorts and clinically normal older adults suggests that the pathophysiological process of AD begins years, if not decades, before the diagnosis of clinical dementia. In addition to alterations affecting the brain, growing evidence suggests the presence of gastrointestinal (GI) comorbidities such as constipation and diarrhea in AD, the underlying pathophysiological process of which remains unknown. The enteric nervous system (ENS) is the intrinsic nervous system of the gastrointestinal tract with neurons organized into microcircuits that allow modulation of GI functions by various neurotransmitters and neurotrophic factors. We recently showed that the neurotrophic factor EphB2, a key molecule regulating neuron connectivity/plasticity in the central nervous system, also regulates the connectivity and activity of ENS neurons by controlling synapse-associated proteins. 

In addition, alterations in the PNS and gastrointestinal dysfunction, ranging from neuron loss to intestinal dysmotility and changes in neurotransmitter expression, have been reported in animal models of AD. Furthemore, deposits of amyloid-β (Aβ) peptide, particularly Aβ1-40 and Aβ1-42 (40 or 42 residues long) forms, which are primarily involved in the formation of amyloid plaques, and its precursor protein βAPP, have also been observed in the intestines of AD patients.
Thus, our research focuses on the gut-brain axis with a particular interest in the gut as a potential early site of Aβ pathology

and alterations in enteric neural connectivity and functional consequences in AD.

The importance of the gut is also demonstrated by the contribution of the microbiota in AD. Indeed, dysbiosis of the gut microbiota has been described in both preclinical models and patients with AD. This dysbiosis of the gut microbiota favors the predominance of pro-inflammatory bacteria that promote inflammation, but also an alteration of beneficial metabolites that can modulate Aβ levels downward. However, the ability of bacterial metabolites to prevent gastrointestinal dysfunction and/or cognitive decline in AD pathology and their mode of action remain largely unknown. 

​There is growing evidence suggesting that intestinal dysbiosis contributes to AD and that the microbiota represents a potential therapeutic target and/or tool focused on bacterial strains and their metabolites. In recent years, bacterial or host extracellular vesicles (EVs) have been recognized as essential mediators of communication and signaling within the body.
Furthermore, the ability of extracellular vesicles derived from anti-inflammatory probiotic bacteria to counteract Aβ pathology, CNS remodeling, and restore gut-brain functions remains to be demonstrated in AD.

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​Some questions addressed in ongoing studies:
1. Does Aβ affect enteric neural connectivity?
2. Does Aβ induce gastrointestinal dysfunction?
3. Can microbiota dysbiosis promote enteric Aβ pathology?
4. Through what mechanisms does the microbiota affect enteric functions in AD?
5. How does the microbiota affect intestinal amyloidosis?
6. Which probiotics or bacterial metabolites can improve or prevent intestinal remodeling in AD?

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​This major research focus of our laboratory receives funding from several sources, including the ANR and PEPR (priority research programs and equipment) within the “directed” component of France 2030, known as “Strategic Investment Funding.” Valentine Moullé (postdoctoral researcher) coordinates projects focusing on the impact of extracellular vesicles from probiotic bacteria on intestinal amyloidosis.