Non-transgenic GI-seeded beta-amyloid mouse model

Late-onset Alzheimer's diseases (AD) contributes to > 90% of AD patients compared to < 1 % of cases in familial AD. Significant amount of funding had been put on research using transgenic models based on beta-amyloid or tau hypothesis. However, in the past decade, all clinical trials based on these research had failed. The cause of late-onset AD is unknown but likely involves environmental factors, including diets, contaminants, stress and other living habits. We believe that a non-transgenic long-term research model is required to represent the > 90% late-onset AD populations for revolutionary research on early diagnostics and new therapeutic treatment strategies. 

Our model based on the brain-gut axis and prion hypothesis

We recently published two leading articles using our newly-developed late-onset AD model of the mouse through injecting soluble oligomeric beta-amyloid (1-42) into the gastrointestinal (GI) wall in 2-month-old young mouse and seeded for a year. The model makes use of misfolded beta-amyloid in the gut to trigger cascades of misfolding of beta-amyloid, and hypothesize to be translocated from the gut to the brain via neuronal, immunological and vascular pathways similar to the prion protein. 
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Evidences we found:

In 4 hours in-vitro tissue culture,
Beta-amyloid was taken-up by myenteric neurons in the colon

In 16 hours in-vitro tissue culture,
​Beta-amyloid induced significant neuronal damage
In 1 month tracking study,
After intra-GI injection of beta-amyloid in-vivo, fluorescently-labelled beta-amyloid:
  • was aggregated in the myenteric plexus.
  • was migrated along the intestine such as reaching the jejunum.
  • induced activated macrophages and dendritic cells
  • was aggregated in vagus nerves
  • was found in the brain with 50% chances
In 6 month long-term in-vivo model,
  • Significant reduction in gut tissue wet weight

In 12 month long-term in-vivo model,
  • Jejunal motility dysfunction in terms of oscillation frequency and neuron coupling
  • Significant memory impairment in the Y-maze alternation task and novel objection recognition task
  • Beta-amyloid aggregation in the vagus nerves and at the hippocampus and cortex

Summary

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References

  1. Alzheimer’s_Association. Alzheimer’s Association 2020 Facts and Figures Report. Alzheimer’s Assoc. 2020
  2. Liu YH, Sun YY, Sommerville N, Ngan MP, Ponomarev ED, Lin G & Rudd JA (2020). Soy flavonoids prevent cognitive deficits induced by intra-gastrointestinal administration of beta-amyloid. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 141 111396.
  3. Sun YY, Sommerville NR, Liu YH, Ngan MP, Poon D, Ponomarev ED, Lu ZB, Kung JS & Rudd JA (2020). Intra-gastrointestinal amyloid-beta 1-42 oligomers perturb enteric function and induce Alzheimer's disease pathology, Journal of Physiology-london, 598(19), 4209-4223.