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

被引：34

作者：

Pellegrini, Carolina ^{[1
]}

Daniele, Simona ^{[1
]}

Antonioli, Luca ^{[2
]}

Benvenuti, Laura ^{[2
]}

D'Antongiovanni, Vanessa ^{[2
]}

Piccarducci, Rebecca ^{[1
]}

Pietrobono, Deborah ^{[1
]}

Citi, Valentina ^{[1
]}

Piragine, Eugenia ^{[1
]}

Flori, Lorenzo ^{[1
]}

Ippolito, Chiara ^{[3
]}

Segnani, Cristina ^{[3
]}

Palazon-Riquelme, Pablo ^{[4
]}

Lopez-Castejon, Gloria ^{[4
]}

Martelli, Alma ^{[1
]}

Colucci, Rocchina ^{[5
]}

Bernardini, Nunzia ^{[3
,6
]}

Trincavelli, Maria Letizia ^{[1
]}

Calderone, Vincenzo ^{[1
]}

Martini, Claudia ^{[1
]}

Blandizzi, Corrado ^{[2
]}

Fornai, Matteo ^{[2
]}

机构：

[1] Univ Pisa, Dept Pharm, I-56126 Pisa, Italy

[2] Univ Pisa, Dept Clin & Expt Med, Unit Pharmacol & Pharmacovigilance, I-56126 Pisa, Italy

[3] Univ Pisa, Dept Clin & Expt Med, Unit Histol & Med Embryol, I-56126 Pisa, Italy

[4] Univ Manchester, Manchester Collaborat Ctr Inflammat Res, Manchester M13 9PL, Lancs, England

[5] Univ Padua, Dept Pharmaceut & Pharmacol Sci, I-35131 Padua, Italy

[6] Univ Pisa, Interdept Res Ctr Nutraceut & Food Hlth, I-56126 Pisa, Italy

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2020年 / 21卷 / 10期

关键词：

Alzheimer's disease; mild cognitive impairment; colonic motility; enteric inflammation; NLRP3; inflammasome; interleukin-1; beta; beta-amyloid protein; tau protein; alpha-synuclein; enteric neuronal coding; mitochondrial function; MILD COGNITIVE IMPAIRMENT; AMYLOID-BETA; ALPHA-SYNUCLEIN; PARKINSONS-DISEASE; EPITHELIAL BARRIER; NERVOUS-SYSTEM; GUT MICROBIOTA; MURINE MODEL; MOUSE MODEL; EXPRESSION;

D O I：

10.3390/ijms21103523

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 A beta, tau proteins, alpha -synuclein and IL-1 beta 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 A beta 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-1 beta, active-caspase-1 expression and eosinophil density; and (3) decreased citrate synthase activity and claudin-1 expression. In THP-1 cells, A beta promoted IL-1 beta release, which was abrogated upon incubation with caspase-1 inhibitor or in ASC(-/-) cells. A beta 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.

引用

页数：28

共 67 条

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