👤 Antonio Masino

The Gastrointestinal (GI) microbiome and gut-brain axis are associated with the progression and pathology of Alzheimer's disease (AD). Amyloid deposition is thought to be a driver of AD, causing synaptic dysfunction and neuronal death in the brain. Chronic constipation is a common gastrointestinal (GI) dysmotility in AD patients, which impacts patient outcomes and quality of life. It is unknown if enteric amyloidosis disrupts myenteric neuron function and causes GI dysmotility. Untreated male and female APP/PS1 (a transgenic murine model of brain amyloidosis) and sex-matched control mice were followed until 12 months of age. A separate cohort of mice was treated with a vehicle or the beta-secretase (BACE1) inhibitor, lanabecestat, starting at 5 months of age until 7 months. GI motility was assessed in all mice by measuring whole GI transit in vivo. Propulsive colonic motility and GI smooth muscle contractions were measured ex vivo. At 7 or 12 months old, amyloidosis in the brain and myenteric plexus was determined by immunohistochemistry or ELISA; the myenteric neural density, including the cholinergic and nitrergic neurons, was evaluated by immune staining and RT-PCR; expression of pro-inflammatory factors in the GI wall was assessed by RT-PCR. By 7 months of age, male and female APP/PS1 mice developed abundant amyloid plaques in the brain. Aged untreated male APP/PS1 mice also demonstrated Aβ deposition in the colonic myenteric ganglia, which was associated with increased fecal output and faster whole GI transit starting at 4-7 months old, but vehicle- and lanabecestat-treated male APP/PS1 mice had similar GI motility to their non-genetic controls until 7 months old. None of the female APP/PS1 mice showed GI dysmotility or myenteric amyloidosis. Two months of lanabecestat treatment effectively reduced amyloid plaque burden in the brains of female APP/PS1 mice but not in male APP/PS1 mice. Treatment with lanabecestat did not affect myenteric Aβ intensity or GI motility in all APP/PS1 mice. All APP/PS1 mice did not show myenteric neuronal degeneration or inflammation until 12 months old. APP/PS1 mice do not recapitulate myenteric amyloidosis persistently and lack the phenotype of constipation observed in human AD patients; these mice should not be considered an adequate murine model for studying the role of myenteric amyloidosis in GI dysmotility. An adequate animal model with myenteric amyloidosis is required for further study. Show less

Lacticaseibacillus paracasei cell wall presents two capsular polysaccharides, CPS-1 and CPS-2, and a teichoic acid. CPS-1 is novel and it presents a branched heptasaccharide repeating unit, with the sequence →6)-α-d-Gal-(1→3)-β-l-Rha-(1→4)-β-d-Glc-(1→3)-α-d-GlcNAc-(1→2)-β-d-Glc-(1→6)-β-d-Glc-(1→ in the linear part to which a β-l-Rha is attached to O-4 of GlcNAc. Regarding CPS-2, its structure was previously reported for L.casei, and it presents the tetrasaccharide repeat 2)-α-l-Rha-(1→2)-α-l-Rha-(1→3)-α-l-Rha-(1→3)-α-d-GalNAc-(1→ as backbone, where the first Rha is substituted with a trisaccharide made of Rha, GlcNAc and Glc, and the third Rha has a Glc as a non-stoichiometric substituent. Preliminary in-vitro immunological analyses disclosed that the two glycans exert different activities. CPS-1 is superior to CPS-2 for the elicitation of IL-33, an interleukin that alerts the immune system to tissue damage or danger. CPS-2 instead is more efficient than CPS-1 in the elicitation of the antimicrobial peptides LL-37 and HBD-2, and it is a strong elicitor of occludin, a protein of the tight junctions relevant for the epithelium integrity. These findings suggest that L.paracasei CPSs play a synergistic and beneficial role in the gut, thus paving the way to studies aimed to examine their mode of action or their exploitation in the prevention and treatment of human gastrointestinal diseases. Show less