P1‐301: Characterization of APPsi transgenic rats for cognitive deficits and brain pathology

Abstract

Alzheimer's disease is one of the most devastating neurodegenerative diseases of the 21st century. Pathological aggregation of the amyloid precursor protein (APP) in the brain of AD patients is thought to be one of the main causes for the observed progressive cognitive decline in affected people. So far, mostly transgenic mouse models are used to mimic the pathology of AD. Some o these models reflect the pathology of AD strikingly well but harbor the disadvantages of mice models in general. We therefore characterized the transgenic rat model by Claudio Cuello and his team (Leon et al. 2010) that expresses the human APP751 cDNA with Swedish (K679N/N671L) and Indiana (V717F) mutations under the regulatory control of the rat Thy-1 promoter. High-APP expressing animals of both sexes were tested over age for behavioral deficits like general health, activity and memory in the open field test, forced swim test, elevated plus maze, Morris water maze, new object recognition and passive avoidance test. Brain, CSF and plasma amyloid β38, 40 and 42 levels were analyzed using the immunosorbent assay MSD-ISA. Brain pathology was assessed immunohistologically for amyloid and amyloid depositions and for brain inflammation i.e. astrogliosis and activated microglia. Our results show that these rats have altered activity levels and memory deficits as measured by different cognitive tests already in early age. Furthermore, amyloid β38, 40 and 42 levels in the cerebrospinal fluid and in the brain of rats increase over age and this can be supported by brain amyloid immunohistochemical results. Accordingly, brain inflammation, which is altered already in the youngest age group, is elevated in all age groups. This transgenic rat model thus not only provides AD specific behavioral deficits but also corresponding brain pathology that starts earl y and increases over age. Since rats are more suitable to perform most behavioral tests compared to mice the APPsi transgenic rat model presents an appropriate alternative to well established transgenic APP mouse models for AD research as well as novel compound tests against AD.