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.

The bowel and beyond: the enteric nervous system in neurological disorders

“…Over 70% of enteric neurons are cholinergic 7 , further supporting the potential effects of AD pathophysiology in the ENS. Transgenic mice that express three mutant forms of APP (Lys670Asn, Met671Leu, and Val717Phe) 116 or APP with a double mutation (Lys670Asn and Met671Leu) plus mutant presenilin1 (PS1-dE9), all of which are associated with familial AD 117 , develop progressive accumulation of Aβ within enteric neurons. This Aβ accumulation is associated with a decrease in numbers of enteric neurons, dysmotility and increased vulnerability to intestinal inflammation, depending on the transgene and promoter used 116,117 .…”

Gut–Brain Axis: Role of Gut Microbiota on Neurological Disorders and How Probiotics/Prebiotics Beneficially Modulate Microbial and Immune Pathways to Improve Brain Functions

“…However, TG mice transplanted with fecal microbiota from WT mice improved the amyloid peptide, p-tau protein level, synaptic plasticity and alternation in gut microbiota composition as compared to WT mice [ 85 ]. In addition, an increased intestinal Aβ load, AβPP, CD68, and p-Tau immunoreactivity was observed in AD patients, as well as in APP/PS1 mice, suggesting that the intestine of AD patients may mimic the brain, and induce inflammatory and immune changes relating to AβPP and Aβ pathology [ 86 ]. Furthermore, the examination of modulatory property prebiotics against AD exhibited that fructooligosaccharides ameliorated cognitive deficits and neurodegeneration in TG APP/PS1 mice by upregulating the levels of PSD-95, synapsin I, and GLP-1 and decreasing the level of p-JNK and GLP1R [ 87 ].…”

Amyloid precursor protein in pancreatic islets

“…However, it is known that higher molecular weight isoforms of APP are present in many peripheral organs (Selkoe et al 1988). Our recent work has focused on characterizing APP expression and function in several peripheral tissues including intestinal and adipose tissue (Puig and Combs 2013; Puig, et al 2015; Puig, et al 2012; Sondag and Combs 2010). …”