Presenilin 1 transgene addition to amyloid precursor protein overexpressing transgenic rats increases amyloid beta 42 levels and results in loss of memory retention

Abstract

BackgroundWe previously reported the production of transgenic rats (APP21 line) that over-express human amyloid precursor protein (APP) containing Swedish and Indiana mutations. In order to generate a better model for Alzheimer’s disease (AD), the APP21 rat line was used to generate double transgenic line that over-expressed Presenilin 1 (PS1) with L166P mutation in addition to APP transgene (APP + PS1 line).ResultsThirty-two double transgenic founders were generated and the ultimate transgenic founder was selected based on PS1 transgene copy number and level of amyloid-beta (Aβ)42 peptide. The APP + PS1 double transgenic rats had 38 times more PS1 in brains compared to APP rats. Behavioral assessment using Barnes maze showed that APP + PS1 rats exhibited a larger learning and memory deficit than APP21 rats. Double transgenic rats also produced more Aβ42. Histological examination of the brains showed that the APP21 rat line displayed neurofibrillary tangles and in contrast, the APP + PS1 line showed chromatolysis in hippocampal neurons and neuronal loss in CA3 region of hippocampus.ConclusionsDue to the separate segregation of APP and PS1 transgenes in APP + PS1 double transgenic rats, this transgenic line may be a valuable model for studying the effects of various levels of APP and PS1 transgenes on various aspects of brain pathologies associated with the AD phenotype.Electronic supplementary materialThe online version of this article (doi:10.1186/s12868-016-0281-8) contains supplementary material, which is available to authorized users.

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

“…An evaluation of error performance found that APP21 and APP+PS1 rats showed poor memory for the location of the escape box during acquisition, retention, and reversal in the Barnes maze compared with the WT rats. This result is consistent with many spatial learning findings using rodent models of AD [ 18 , 19 , 20 , 21 ], including performance in the Barnes maze [ 9 , 12 , 13 , 14 , 15 , 22 , 23 ].…”

“…However, surprisingly, the WT animals had significantly longer latencies than APP+PS1 animals during acquisition training and had a tendency towards longer latencies during reversal training. This trend was unexpected because previous studies with these models arrived at the opposite conclusion and found that WT had the shortest latencies and APP+PS1 rats had the longest latencies [ 9 ]. The current finding may have stemmed from differential levels of motivation; it is possible that the WT animals were no longer sufficiently aversively stimulated by the Barnes maze environment and thus unmotivated to complete the maze.…”

“…Contrary to many mouse models of AD, APP21 rats that overexpress human APP using the Swedish and Indiana mutations do not produce Aβ plaques in their brains [ 8 ]. To induce plaques, the APP21 model was used to generate a double transgenic rat that overexpresses both human APP and PS1 (APP+PS1) [ 9 ]. Based on previous studies that have found greater behavioral impairment and pathology in females across multiple transgenic (Tg) mouse models and recognizing the notion that females may be inherently more vulnerable than males to AD pathogenesis [ 10 ], the focus of the current study was to characterize the behavioral symptoms and pathology of older female APP+PS1 rats.…”

“…This maze is particularly well-suited to examining learning in animal models of AD because it does not rely on appetitive motivation and is considered to be less stressful than other common tasks like the Morris water maze [ 11 ]. Previous research found that Tg animals display poor spatial learning in the Barnes maze task compared to their wild-type littermates in a variety of AD mouse models, including TgCRND8 [ 12 ], 3xTg [ 13 ], APPswe/PS1ΔE9 [ 14 , 15 ] as well as the APP21 and APP+PS1 rats [ 9 ]. After behavioral testing, the brains from a subset of animals were analyzed for the presence of Aβ plaques and tau using immunohistochemistry.…”

Rodent Models of Amyloid-Beta Feature of Alzheimer’s Disease: Development and Potential Treatment Implications

“…The APP+PS1 rat expressing human APP with Swedish and Indiana mutations and human PS1 with L166P mutation was generated by injecting a lentiviral vector containing PSEN1 into the fertilized egg of homozygous APP21 rats [113]. Compared to APP21 rats, APP+PS1 rats had approximately two times the level of Aβ and more severe amyloid pathology, as well as memory and learning deficits that resembled AD [113]. At 10 months, APP+PS1 rats displayed cognitive declines in various areas such as acquisition, retention, and reversal phase as shown in the Barnes maze task [113].…”