title: Overexpression of mutant amyloid-β protein precursor and presenilin 1 modulates enteric nervous system.
abstract: Alzheimer's disease (AD) is a neurodegenerative disorder histologically characterized by amyloid-β (Aβ) protein accumulation and activation of associated microglia. Although these features are well described in the central nervous system, the process and consequences of Aβ accumulation in the enteric nervous system have not been extensively studied. We hypothesized that Aβ also may accumulate in the enteric nervous system and lead to immune cell activation and neuronal dysfunction in the digestive tract not unlike that observed in diseased brain. To test this hypothesis, ileums of the small intestine of thirteen month old AβPP/PS1 and C57BL/6 (wild type) mice were collected and analyzed using immunohistochemistry, western blot analysis, cytokine arrays, and ELISA. AβPP/PS1 mice demonstrated no differences in intestinal motility or water absorption but elevated luminal IgA levels compared to wild type mice. They also had increased protein levels of AβPP and the proteolytic enzyme, BACE, corresponding to an increase in Aβ1-40 in the intestinal lysate as well as an increase in both Aβ1-40 and Aβ1-42 in the stool. This correlated with increased protein markers of proinflammatory and immune cell activation. Histologic analysis localized AβPP within enteric neurons but also intestinal epithelial cells with elevated Aβ immunoreactivity in the AβPP/PS1 mice. The presence of AβPP, Aβ, and CD68 immunoreactivity in the intestines of some patients with neuropathologically-confirmed AD are consistent with the findings in this mouse model. These data support the hypothesis that in AD the intestine, much like the brain, may develop proinflammatory and immune changes related to AβPP and Aβ.
authors.affiliation: Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA.
authors.forename: Kendra L
authors.initials: KL
authors.lastname: Puig
authors.affiliation: Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA.
authors.forename: Brianna M
authors.initials: BM
authors.lastname: Lutz
authors.affiliation: Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA.
authors.forename: Siri A
authors.initials: SA
authors.lastname: Urquhart
authors.affiliation: Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Rebel
authors.affiliation: Department of Pathology, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA.
authors.forename: Xudong
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA.
authors.forename: Gunjan D
authors.initials: GD
authors.lastname: Manocha
authors.affiliation: Department of Pathology, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA.
authors.forename: MaryAnn
authors.initials: M
authors.lastname: Sens
authors.affiliation: Division of Gastroenterology, University of Utah, Salt Lake City, UT, USA.
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Tuteja
authors.affiliation: Center for Alzheimer's Care, Imaging and Research, Department of Neurology, University of Utah, Salt Lake City, UT, USA.
authors.forename: Norman L
authors.initials: NL
authors.lastname: Foster
authors.affiliation: Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA.
authors.forename: Colin K
authors.initials: CK
authors.lastname: Combs
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D016207:Cytokines; D004195:Disease Models, Animal; D017615:Enteric Nervous System / Q000378:metabolism* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D053764:Presenilin-1 / Q000235:genetics*
chemical_list: D016564:Amyloid beta-Protein Precursor; D016207:Cytokines; C508853:PSEN1 protein, human; D053764:Presenilin-1
keywords: Amyloid-β; cytokines; inflammation; intestine