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Dysregulated Gut Homeostasis Observed Prior to the Accumulation of the Brain Amyloid-? in Tg2576 Mice.


ABSTRACT: Amyloid plaques in Alzheimer's disease (AD) are associated with inflammation. Recent studies demonstrated the involvement of the gut in cerebral amyloid-beta (A?) pathogenesis; however, the mechanisms are still not well understood. We hypothesize that the gut bears the A? burden prior to brain, highlighting gut-brain axis (GBA) interaction in neurodegenerative disorders. We used pre-symptomatic (6-months) and symptomatic (15-months) Tg2576 mouse model of AD compared to their age-matched littermate WT control. We identified that dysfunction of intestinal epithelial barrier (IEB), dysregulation of absorption, and vascular A? deposition in the IEB occur before cerebral A? aggregation is detectible. These changes in the GBA were associated with elevated inflammatory plasma cytokines including IL-9, VEGF and IP-10. In association with reduced cerebral myelin tight junction proteins, we identified reduced levels of systemic vitamin B12 and decrease cubilin, an intestinal B12 transporter, after the development of cerebral A? pathology. Lastly, we report A? deposition in the intestinal autopsy from AD patients with confirmed cerebral A? pathology that is not present in intestine from non-AD controls. Our data provide evidence that gut dysfunction occurs in AD and may contribute to its etiology. Future therapeutic strategies to reverse AD pathology may involve the early manipulation of gut physiology and its microbiota.

SUBMITTER: Honarpisheh P 

PROVIDER: S-EPMC7084806 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Dysregulated Gut Homeostasis Observed Prior to the Accumulation of the Brain Amyloid-β in Tg2576 Mice.

Honarpisheh Pedram P   Reynolds Caroline R CR   Blasco Conesa Maria P MP   Moruno Manchon Jose F JF   Putluri Nagireddy N   Bhattacharjee Meenakshi B MB   Urayama Akihiko A   McCullough Louise D LD   Ganesh Bhanu P BP  

International journal of molecular sciences 20200303 5


Amyloid plaques in Alzheimer's disease (AD) are associated with inflammation. Recent studies demonstrated the involvement of the gut in cerebral amyloid-beta (Aβ) pathogenesis; however, the mechanisms are still not well understood. We hypothesize that the gut bears the Aβ burden prior to brain, highlighting gut-brain axis (GBA) interaction in neurodegenerative disorders. We used pre-symptomatic (6-months) and symptomatic (15-months) Tg2576 mouse model of AD compared to their age-matched litterma  ...[more]

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2019-07-01 | GSE106643 | GEO