Intra-gastrointestinal amyloid-β1-42 oligomers perturb enteric function and induce Alzheimer's disease pathology.

Alzheimer's disease (AD) is the most common age-related cause of dementia, characterised by extracellular beta-amyloid (Aβ) plaques and intracellular phosphorylated tau tangles in the brain. Aβ deposits have also been observed in the gastrointestinal (GI) tract of AD patients and transgenic mice, with overexpression of amyloid precursor protein. In the present studies, we investigate whether intra-GI administration of Aβ can potentially induce amyloidosis in the central nervous system (CNS) and AD-related pathology such as dementia. We micro-injected Aβ1-42 oligomers (4 μg per site, five sites) or vehicle (saline, 5 μl) into the gastric wall of ICR mice under general anaesthesia. Immunofluorescence staining and in vivo imaging showed that HiLyte Fluor 555-labelled Aβ1-42 had migrated within 3 h via the submucosa to nearby areas and was internalised into cholinergic neurons. At 1 month, HiLyte Fluor 555-labelled Aβ1-42 in the body of the stomach and proximal colon had partly re-distributed to the fundus and jejunum. At 1 year, the jejunum showed functional alterations in neuromuscular coupling (P < 0.001), and Aβ deposits were present in the vagus and brain, with animals exhibiting cognitive impairments in the Y-maze spontaneous alteration test (P < 0.001) and the novel object recognition test (P < 0.001). We found that enteric Aβ oligomers induce an alteration in gastric function, amyloidosis in the CNS, and AD-like dementia via vagal mechanisms. Our results suggest that Aβ load is likely to occur initially in the GI tract and may translocate to the brain, opening the possibility of new strategies for the early diagnosis and prevention of AD.