Abstract
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.
Highlights
Ageing-related cognitive disorders, including age-associated memory impairment (AAMI), mild cognitive impairment (MCI) and senile dementia, have become common health threats to the elderly population
Our results show that SAMP8 mice displayed an impairment of cognitive and motor functions along with a significant decrease in faecal output starting from six months of age, indicating that, in SAMP8 animals, the alterations of colonic motility appear in the prodromal phase of Alzheimer’s disease (AD), before the full development of central nervous system (CNS) pathology
The present study provides evidence that, in the SAMP8 AD model, cognitive dysfunctions are associated with enteric AD-related protein accumulation and their heterocomplexes, colonic inflammation, mitochondrial dysfunction, altered intestinal epithelial barrier (IEB) and impaired excitatory cholinergic and tachykininergic neurotransmission, which may all contribute to bowel motor dysfunctions since the earliest stages of the disease, before the full development of brain pathology
Summary
Ageing-related cognitive disorders, including age-associated memory impairment (AAMI), mild cognitive impairment (MCI) and senile dementia, have become common health threats to the elderly population. Changes in gut microbiota composition and impairments of the intestinal epithelial barrier (IEB) could determine the accumulation of enteric Aβ and phosphorylated tau (p-tau) proteins, which, in turn, could trigger enteric and peripheral neurogenic/inflammatory responses, and contribute to bowel motor disturbances as well as CNS neuroinflammation and neurodegeneration via gut–brain ascending pathways [4,5] Both pre-clinical and human studies have shown that AD is associated with several changes in gut microbiota composition, signs of enteric inflammation as well as colonic accumulation of Aβ and p-tau tangle-like structures, which could lead to intestinal motor dysfunctions [6,7,8,9]. The relationship between onset of cognitive impairment and bowel inflammation, colonic dysmotility and AD-related proteins before the full development of brain pathology remains to be explored in depth
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