Research Article: Constipation in Tg2576 mice model for Alzheimer’s disease associated with dysregulation of mechanism involving the mAChR signaling pathway and ER stress response

Date Published: April 12, 2019

Publisher: Public Library of Science

Author(s): Ji Eun Kim, Jin Ju Park, Mi Rim Lee, Jun Young Choi, Bo Ram Song, Ji Won Park, Mi Ju Kang, Hong Joo Son, Jin Tae Hong, Dae Youn Hwang, Yi Hu.

http://doi.org/10.1371/journal.pone.0215205

Abstract

Although constipation has been researched in various neurological disorders, including Parkinson’s disease (PD) and spinal cord injury (SCI), the pathological mechanism of this symptom has not been investigated in Alzheimer’s disease (AD) associated with loss of nerve cells in the brain. This study was undertaken to gain scientific evidences for a molecular correlation between constipation and AD.

To understand the etiology, we measured alterations in various constipation parameters, muscarinic acetylcholine receptors (mAChRs) and endoplasmic reticulum (ER) stress response, in 11-month-old Tg2576 transgenic (Tg) mice showing AD-like phenotypes.

A high accumulation of amyloid beta (Aβ) peptides, a key marker of AD pathology, were detected in the cortex and hippocampus of Tg mice. Furthermore, significant alterations were observed in various constipation parameters including stool weight, histological structure, cytological structure and mucin secretion in Tg2576 mice. Moreover, M2 and M3 expression and the downstream signaling pathways of mAChRs were decreased in the Tg group, as compared with non-Tg (NT) group. Furthermore, activation of ER stress proteins and alteration of ER structure were also detected in the same group.

The results of the present study provide strong novel evidence that the neuropathological constipation detected in Tg2576 mice is linked to dysregulation of the mAChR signaling pathways and ER stress response.

Partial Text

Constipation is an acute or chronic gastrointestinal disease characterized by infrequent bowel movements, hard and dry feces, incomplete bowel evacuation and difficulty during defecation [1–3]. Clinically, this disease is diagnosed with physical examinations (including feces for analysis) and careful rectal examination, as well as four key physiological examinations such as colonic-transit testing, anorectal manometry, balloon expulsion and defecography [4, 5]. Also, various physiological, genetic and environmental factors may contribute towards acute and chronic constipation. In most cases, acute constipation is induced by bowel obstruction, adynamic ileus and some drug administrations, whereas chronic constipation could result due to colonic tumors, metabolic disorders, central nervous system disorders, peripheral nervous system disorders, systemic disorders, functional disorders, and dietary factors [6–7].

AD is the most common form of dementia in elderly people, having an estimated worldwide incidence of 35.6 million patients in 2010, which is projected to nearly double every 20 years [40]. Patients suffering from dementia often have accompanying chronic diseases. An inverse epidemiological correlation between AD and cancer has been revealed in multiple ethnic groups [41]. Diabetic patients (type 2) have a higher risk of eventually developing AD or other dementias [42]. Recent researches are therefore rapidly increasing to identify novel evidences for correlations between AD and other diseases. As part of our studies using the Tg mice model for AD, we investigated whether the AD pathological condition affects the gastrointestinal function and physiology. Although the current results provide initial clues about the association between two chronic diseases, further studies are required to investigate the relevant mechanism of action.

The results of the present study suggest that the AD pathological condition induces constipation through alteration of the excretion parameters as well as changes in the histological structure, mucin secretion, mAChRs downstream signaling pathway and ER stress response of the colon. The results of the present study suggest that the AD pathological condition induces constipation through alteration of the excretion parameters as well as changes in the histological structure, mucin secretion, mAChRs downstream signaling pathway and ER stress response of the colon. These results also demonstrate that constipation should be considered an important symptom of the AD and must be taken into acount for any potential treatment.

 

Source:

http://doi.org/10.1371/journal.pone.0215205

 

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