Changes of the Enteric Nervous System in Amyloid-β Protein Precursor Transgenic Mice Correlate with Disease Progression

Article type: Research Article

Authors: Semar, Sandra^{a; 1} | Klotz, Markus^{a; 1} | Letiembre, Maryse^{b; 1} | Van Ginneken, Chris^c | Braun, Anne^a | Jost, Viktor^a | Bischof, Michael^a | Lammers, Wim J.^e | Liu, Yang^b | Fassbender, Klaus^b | Wyss-Coray, Tony^d | Kirchhoff, Frank^f | Schäfer, Karl-Herbert^{a; g; *}

Affiliations: [a] Department of Biotechnology, University of Applied Sciences Kaiserslautern, Zweibrücken, Germany | [b] Department of Neurology, University of Saarland, Saarbrücken, Germany | [c] Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium | [d] Department of Neuropathology, Stanford School of Medicine, Stanford, CA, USA | [e] Department of Physiology, UAE University, Al-Ain, United Arab Emirates | [f] Department of Physiology, University of Saarland, Saarbrücken, Germany | [g] Department of Pediatric Surgery, University of Mannheim, Mannheim, Germany

Correspondence: [*] Correspondence to: Karl-Herbert Schäfer, Department of Biotechnology, University of Applied Sciences Kaiserslautern, Amerikastr. 1, D-66482 Zweibrücken, Germany. Tel.: +49 6332 914 418, Fax: +49 6332 914 305, E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: In Alzheimer's disease (AD), fatal neuronal cell loss occurs long before relevant evidence can lead to a reliable diagnosis. If characteristic pathological alterations take place in the enteric nervous system (ENS), it could be one of the most promising targets for an early diagnosis, using submucosal biopsies from the gut. We therefore investigated time- and spatial-dependent changes in an amyloid-β protein precursor (AβPP) overexpressing transgenic mouse model to examine early changes within the ENS. Wholemount preparations and paraffin sections were analyzed for the expression of neuronal, glial, and innate immunity markers. Isolated myenteric networks were screened for differences in overall protein expression, and a motility analysis delivered functional data. The level of AβPP in the gut was significantly higher in the AD mouse model than in wild-type mice and also higher in the gut than in the brain at all ages investigated. The transcriptional level of Nestin, GFAP, and TLR4 increased with age with a peak at 3 months. At the protein level, human amyloid-β was located in myenteric neurons. Myenteric networks showed a reduction of the neuronal density in AβPP compared to wild-type mice, which was functionally relevant as revealed by motility analysis. The ENS undergoes significant changes during the early onset of AβPP expression in AD mouse models that appear before those seen in the brain as demonstrated in this study. Thus, there is a chance of determining similar alterations in the human gut of AD patients, which could be used to develop early diagnostic approaches.

Keywords: Alzheimer's disease, amyloid-β protein precursor, enteric nervous system, potential biomarker

DOI: 10.3233/JAD-120511

Journal: Journal of Alzheimer's Disease, vol. 36, no. 1, pp. 7-20, 2013