Memory deficiency, cerebral amyloid angiopathy, and amyloid-β plaques in APP+PS1 double transgenic rat model of Alzheimer’s disease

Diana Klakotskaia,Edward G Stopa,Cansu Agca,Rachel A Richardson,Yuksel Agca,Todd R Schachtman,Stephen D Ginsberg

doi:10.1371/journal.pone.0195469

Diana Klakotskaia, Edward G Stopa + Show 5 more

Open Access

https://doi.org/10.1371/journal.pone.0195469

Copy DOI

Abstract

Transgenic rat models of Alzheimer’s disease were used to examine differences in memory and brain histology. Double transgenic female rats (APP+PS1) over-expressing human amyloid precursor protein (APP) and presenilin 1 (PS1) and single transgenic rats (APP21) over-expressing human APP were compared with wild type Fischer rats (WT). The Barnes maze assessed learning and memory and showed that both APP21 and APP+PS1 rats made significantly more errors than the WT rats during the acquisition phase, signifying slower learning. Additionally, the APP+PS1 rats made significantly more errors following a retention interval, indicating impaired memory compared to both the APP21 and WT rats. Immunohistochemistry using an antibody against amyloid-β (Aβ) showed extensive and mostly diffuse Aβ plaques in the hippocampus and dense plaques that contained tau in the cortex of the brains of the APP+PS1 rats. Furthermore, the APP+PS1 rats also showed vascular changes, including cerebral amyloid angiopathy with extensive Aβ deposits in cortical and leptomeningeal blood vessel walls and venous collagenosis. In addition to the Aβ accumulation observed in arterial, venous, and capillary walls, APP+PS1 rats also displayed enlarged blood vessels and perivascular space. Overall, the brain histopathology and behavioral assessment showed that the APP+PS1 rats demonstrated behavioral characteristics and vascular changes similar to those commonly observed in patients with Alzheimer’s disease.

Highlights

Alzheimer’s disease (AD) is one of the most devastating and costly diseases in the world and currently affects over 5.5 million Americans [1]
Anxiety levels were not measured in this study, other studies have found that Tg animals tend to have higher levels of anxiety [18, 24, 25, 26] and it is possible that APP21 and amyloid precursor protein (APP)+presenilin 1 (PS1) rats continue to be motivated to escape the aversive nature of the Barnes maze even after many training
The current findings suggest that over-expression of APP on its own may result in neuronal pathology and a learning deficit and that Aβ plaques and cerebral amyloid angiopathy (CAA) may not be required for such behavioral impairment

Summary

Methods

The APP21 and APP+PS1 rats were littermates and were bred and born in the facility in which the experiments were performed. All of the Tg rats were homozygous for the human APP transgene. In addition to the APP transgene, the APP+PS1 rats were hemizygous for the human PS1 transgene. The wild type Fischer 344 (WT) rats were purchased from Envigo (Indianapolis, IN) at 4 weeks of age. Rats were housed in conventional cages at 20–25 ̊C with free access to food and water and all of the animal studies performed were approved by the University of Missouri’s Animal Care and Use Committee and were in accordance with the guidelines of the Institute for Laboratory Animal Research Guide for the Care and Use of Laboratory Animals

Results

Discussion

Conclusion