Temporal progression of Alzheimer's disease in brains and intestines of transgenic mice.

The amyloid beta (Aβ) peptide is associated with the neurodegenerative and inflammatory changes in brains affected by Alzheimer's disease (AD). We hypothesized that the enteric nervous system also produces Aβ in an intestinal component of disease. To test this idea, we compared C57BL/6 wild-type (WT) male and female mice to two models of Alzheimer's disease, amyloid precursor protein (APP)/presenilin 1 (PS1) mice and amyloid precursor protein NL-G-F (AppNL-G-F) mice, at 3, 6, and 12 months of age. Brain Aβ plaque deposition in AppNL-G-F mice preceded that in the APP/PS1 mice, observable by 3 months. Three-month-old female AppNL-G-F mice had decreased intestinal motility compared with WT and APP/PS1 mice. However, 3-month-old female APP/PS1 mice demonstrated increased intestinal permeability compared with WT and AppNL-G-F mice. Both sexes of APP/PS1 and AppNL-G-F mice demonstrated increased colon lipocalin 2 mRNA and insoluble Aβ 1-42 levels at 3 months. These data demonstrate an unrecognized enteric aspect of disease in 2 different mouse models correlating with the earliest brain changes.