New Genetically Engineered Rat Model Can Aid Alzheimer’s Research, Study Says

A rat model genetically engineered to express high levels of two genes can help researchers learn more about the disease mechanisms that lead to Alzheimer’s disease, a new study shows.

The study, “Memory deficiency, cerebral amyloid angiopathy, and amyloid-β plaques in APP+PS1 double transgenic rat model of Alzheimer’s disease,” was published in the journal PLOS One.

The amyloid precursor protein (APP) produces small protein molecules called amyloid-β (Aβ) peptides. These Aβ peptides progressively accumulate and form plaques in the brain, leading to the development of Alzheimer’s.

Mutations in the presenilin 1 (PS1) gene are known to result in early-onset Alzheimer’s and can lead to the overproduction of Aβ42, one of the major types of Aβ peptides.

Animal models are a great tool for investigating the role of specific gene mutations in Alzheimer’s, but few of them exist to study the disease. For this purpose, University of Missouri researchers recently engineered rats with human APP and PS1 proteins.

To better characterize this rat model, they carried out a series of tests to determine behavioral assessment and pathology of older female rats.

To assess behavior in these animals, researchers used a test called the Barnes maze — which relies on tasks carried out by the hippocampus, an area of the brain that plays an important role in the consolidation of information from short-term memory to long-term memory, and in spatial memory. In Alzheimer’s disease, the hippocampus is one of the first regions of the brain to suffer damage.

Results showed that APP+PS1 rats made significantly more errors in the Barnes maze than healthy rats during a part of the maze known as the acquisition phase, indicating they were slower learners.

Additionally, APP+PS1 rats made significantly more errors following a part of the maze known as the retention interval, indicating their memories were impaired.

Researchers also looked at the presence of amyloid-β plaques in the rats’ brains, and found that APP+PS1 rats had extensive and dense amyloid-β plaques across multiple areas of the brain, indicating significant Alzheimer’s pathology.

Furthermore, these animals also showed changes associated with the cardiovascular system. In particular, APP+PS1 rats had severe cerebral amyloid angiopathy — high levels of amyloid-β deposits in the walls of certain blood vessels — a condition prevalent in human Alzheimer’s patients.

Overall, brain pathology and behavioral assessments suggested that these genetically modified animals had similar behavioral characteristics and vascular changes to those commonly observed in Alzheimer’s patients.

“We found that these rat models could be useful in the fight against Alzheimer’s in people,” Yuksel Agca, PhD, an associate professor of veterinary pathology and a researcher in the comparative medicine program at the MU College of Veterinary Medicine, said in a press release.

“Because of their shorter lifespans and their larger size, translational models such as rats are extremely helpful in ongoing studies of disease. The results can be translatable to humans in identifying targets for drugs as well as identifying everyday lifestyle changes we can make to help stave off disorders like Alzheimer’s. We hope this model will become beneficial as research continues to move forward.”