Prodromal Intestinal Events in Alzheimer's Disease (AD): Colonic Dysmotility and Inflammation Are Associated with Enteric AD-Related Protein Deposition

• Published in: International journal of molecular sciences Vol. 21; no. 10; p. 3523
• Main Authors: Pellegrini, Carolina, Daniele, Simona, Antonioli, Luca, Benvenuti, Laura, D'Antongiovanni, Vanessa, Piccarducci, Rebecca, Pietrobono, Deborah, Citi, Valentina, Piragine, Eugenia, Flori, Lorenzo, Ippolito, Chiara, Segnani, Cristina, Palazon-Riquelme, Pablo, Lopez-Castejon, Gloria, Martelli, Alma, Colucci, Rocchina, Bernardini, Nunzia, Trincavelli, Maria Letizia, Calderone, Vincenzo, Martini, Claudia, Blandizzi, Corrado, Fornai, Matteo
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 15-05-2020; MDPI
• Subjects: Age; alpha-Synuclein - metabolism; Alzheimer Disease - pathology; Alzheimer Disease - physiopathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Animals; CARD Signaling Adaptor Proteins - metabolism; Caspase 1 - metabolism; Caspase-1; Citrate synthase; Claudin-1 - metabolism; Cognition; Cognitive ability; Colon - pathology; Colon - physiopathology; colonic motility; Dementia; Deposition; Early childhood education; enteric inflammation; Enzyme-linked immunosorbent assay; Eosinophils - pathology; Evaluation; Feces; Feeding Behavior; Gastrointestinal Motility; Humans; IL-1β; Immunohistochemistry; Impairment; Inflammasomes - metabolism; Inflammation; Inflammation - pathology; Interleukin-1beta - metabolism; interleukin-1β; Intestinal Mucosa - pathology; Intestine; Leukocytes (eosinophilic); Memory; Mice; Microbiota; mild cognitive impairment; Mitochondria; Mitochondria - metabolism; Motility; Nerve Tissue Proteins - metabolism; Neurotransmission; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3 inflammasome; Older people; Pathology; Prodromal Symptoms; Protein Aggregates; Proteins; Senescence; Spectrophotometry; Synuclein; Tau protein; tau Proteins - metabolism; THP-1 Cells; Western blotting; enteric neuronal coding; mitochondrial function; Alzheimer’s disease; colonic motility; β-amyloid protein; mild cognitive impairment; NLRP3 inflammasome; tau protein; α-synuclein; enteric inflammation; interleukin-1β
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21103523

Increasing evidence suggests that intestinal dysfunctions may represent early events in Alzheimer's disease and contribute to brain pathology. This study examined the relationship between onset of cognitive impairment and colonic dysfunctions in a spontaneous AD model before the full development of brain pathology. SAMP8 mice underwent Morris water maze and assessment of faecal output at four, six and eight months of age. In vitro colonic motility was examined. Faecal and colonic Aβ, tau proteins, α-synuclein and IL-1β were assessed by ELISA. Colonic citrate synthase activity was assessed by spectrophotometry. Colonic NLRP3, caspase-1 and ASC expression were evaluated by Western blotting. Colonic eosinophil density and claudin-1 expression were evaluated by immunohistochemistry. The effect of Aβ on NLRP3 signalling and mitochondrial function was tested in cultured cells. Cognitive impairment and decreased faecal output occurred in SAMP8 mice from six months. When compared with SAMR1, SAMP8 animals displayed: (1) impaired in vitro colonic contractions; (2) increased enteric AD-related proteins, IL-1β, active-caspase-1 expression and eosinophil density; and (3) decreased citrate synthase activity and claudin-1 expression. In THP-1 cells, Aβ promoted IL-1β release, which was abrogated upon incubation with caspase-1 inhibitor or in ASC
cells. Aβ decreased mitochondrial function in THP-1 cells. In SAMP8, enteric AD-related proteins deposition, inflammation and impaired colonic excitatory neurotransmission, occurring before the full brain pathology development, could contribute to bowel dysmotility and represent prodromal events in AD.